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b

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WTM □
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c

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d

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e

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**Extended Data Fig. 6** | Transcriptome analysis of BALF NKG2R' NK cells.

(a) Top: PCA shows the clustering pattern of WTM and HC samples. Red circles represent WTM, and gray circles represent HC. Each PCA plot indicates the specific comparison performed. Bottom: Volcano plots highlight genes significantly up-regulated and down-regulated in various comparisons, using p-values instead of Padj. Horizontal lines represent p-value = 0.05, and vertical lines indicate log2 fold change >1 or <-1.
(b) Comparison of MFI for various markers on BALF NKG2R' NK cells isolated from HC, WTM, and OM at least 221 days p.i.
(c) Spearman correlation analysis between NKG2R MFI on BALF NKG2R' NK cells from WTM and OM isolated at least 221 days p.i. and Spike'

Mac measured as in Fig. 2. (d) Comparison of NKG2R<sup>lo</sup>CD16<sup>-</sup>, NKG2R<sup>hi</sup>CD16<sup>-</sup>, NKG2R<sup>lo</sup>CD16<sup>+</sup>, and NKG2R<sup>lo</sup>CD16<sup>+</sup> populations among bulk NK cells, measured on BALF NKG2R' NK cells from HC, WTM, and OM isolated at least 221 days p.i. (e) Spearman correlation between the frequency of NKG2R<sup>lo</sup>CD16<sup>-</sup>, NKG2R<sup>hi</sup>CD16<sup>-</sup>, and NKG2R<sup>lo</sup>CD16<sup>+</sup> populations among bulk NK cells (as in (d) and Spike'). Mac measured as in Fig. 2. For all Spearman correlations, the black solid line represents linear regression, and dotted lines indicate the confidence interval (95%). Symbols represent individual macaques, bars indicate medians, and interquartile ranges are shown. p-Values were determined by Kruskal-Wallis test with Dunn's post-test.
<figure><img src="image_84.png" /><figcaption>b</figcaption></figure>

<figure><img src="image_85.png" /></figure>

NKG2R+ NK cells

<figure><img src="image_86.png" /><figcaption>c</figcaption></figure>

<figure><img src="image_87.png" /><figcaption>d</figcaption></figure>

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Extended Data Fig. 7 | See next page for caption.
b

a

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Extended Data Fig. 7 | See next page for caption.
**Extended Data Fig. 7** | SARS-CoV-2 spike protein binding on lymphocytes.

(a) Representative flow cytometry plots showing the gating strategy for trimeric spike surface staining on total BALF cells from HC, WTM, and OM at ≥221 days p.i. Populations are defined based on specific marker expression. (b) Dot plot illustrating the percentage of surface trimeric spike staining on CD4⁺T cells, CD8⁺T cells, and NKG2R⁺NK cells from HC, WTM, and OM. Dot plots are color-coded for clarity. (c) Left: graph displaying the percentage of CD20⁺B cells positive for trimeric spike surface staining in total BALF cells from HC, WTM, and OM at ≥221 Days p.i. Right: positive Spearman correlation between the percentage of cells

stained with trimeric spike among BALF CD20⁺B cells and the amount of IgG anti-RBD measured in the plasma as in Fig. 1. (d) Graph showing the percentage of CD4⁺T cells, CD8⁺T cells, and NK cells positive for trimeric spike surface staining in BALF cells from HC, WTM, and OM at ≥221 Days p.i. In Spearman correlation, the black solid line represents linear regression, and the dotted line indicates the confidence interval (95%). Each point is labeled with the corresponding monkey's name. In each graph, dots, squares, or triangles represent individual monkeys, bars indicate medians, and interquartile ranges are shown. p-Values were determined using a Kruskal-Wallis test with Dunn's post-test.
**Extended Data Fig. 7** | SARS-CoV-2 spike protein binding on lymphocytes.

(a) Representative flow cytometry plots showing the gating strategy for trimeric spike surface staining on total BALF cells from HC, WTM, and OM at ≥221 days p.i. Populations are defined based on specific marker expression. (b) Dot plot illustrating the percentage of surface trimeric spike staining on CD4⁺T cells, CD8⁺T cells, and NKG2R⁺NK cells from HC, WTM, and OM. Dot plots are color-coded for clarity. (c) Left: graph displaying the percentage of CD20⁺B cells positive for trimeric spike surface staining in total BALF cells from HC, WTM, and OM at ≥221 Days p.i. Right: positive Spearman correlation between the percentage of cells

stained with trimeric spike among BALF CD20⁺B cells and the amount of IgG anti-RBD measured in the plasma as in Fig. 1. (d) Graph showing the percentage of CD4⁺T cells, CD8⁺T cells, and NK cells positive for trimeric spike surface staining in BALF cells from HC, WTM, and OM at ≥221 Days p.i. In Spearman correlation, the black solid line represents linear regression, and the dotted line indicates the confidence interval (95%). Each point is labeled with the corresponding monkey's name. In each graph, dots, squares, or triangles represent individual monkeys, bars indicate medians, and interquartile ranges are shown. p-Values were determined using a Kruskal-Wallis test with Dunn's post-test.
a

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b

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Extended Data Fig. 8 | See next page for caption.
a

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b

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Extended Data Fig. 8 | See next page for caption.
**Extended Data Fig. 8** | NK cell responses after exposure to SARS-CoV-2 spike protein. (a) Representative dot plot illustrating the percentage of intracellular GzmB or IFN-γ in NK cells obtained from BALF of HC, WTM, and OM at ≥ 221 days p.i following 24 hours of culture exposed or non-exposed to trimeric spike protein. The red and purple light squares around the dot plot delineate the WTM (n = 10) and OM (n = 10) convalescent monkey groups, respectively.

(b) Comparative analysis of intracellular GzmB or IFN-γ between NKG2R<sup>hi</sup> and NKG2R<sup>lo</sup> NK cells, following 24 hours of exposure to trimeric spike protein. Each symbol represents an individual monkey, and the median along with the interquartile range is depicted. The p-value was determined using the Wilcoxon matched-pairs signed rank test.
**Extended Data Fig. 8** | NK cell responses after exposure to SARS-CoV-2 spike protein. (a) Representative dot plot illustrating the percentage of intracellular GzmB or IFN-γ in NK cells obtained from BALF of HC, WTM, and OM at ≥ 221 days p.i following 24 hours of culture exposed or non-exposed to trimeric spike protein. The red and purple light squares around the dot plot delineate the WTM (n = 10) and OM (n = 10) convalescent monkey groups, respectively.

(b) Comparative analysis of intracellular GzmB or IFN-γ between NKG2R<sup>hi</sup> and NKG2R<sup>lo</sup> NK cells, following 24 hours of exposure to trimeric spike protein. Each symbol represents an individual monkey, and the median along with the interquartile range is depicted. The p-value was determined using the Wilcoxon matched-pairs signed rank test.
<figure><img src="image_93.png" /><figcaption>b</figcaption></figure>

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<figure><img src="image_99.png" /><figcaption>e</figcaption></figure>

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<figure><img src="image_101.png" /><figcaption>g</figcaption></figure>

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Extended Data Fig. 9 | See next page for caption.
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Extended Data Fig. 9 | See next page for caption.
**Extended Data Fig. 9 | Identifying HLA-E Binding Potential in SARS-CoV-2 Signal Peptides.** (a) Literature-based scheme summarizing peptide processing via TAP-dependent and TAP-independent pathways. (b) In silico analysis predicting signal peptide presence in spike proteins and their cleavage sites, with SignalP 6.0 software suggesting cleavage by Signal peptidase (SP) and Signal peptide peptidase (SPP). Signal peptides comprise hydrophobic core (h region), polar C-terminal end (c region), and polar N-terminal region (n region). (c) Schematic displaying four overlapping nonamers in the 5' region of SARS-CoV-2 signal peptide (PODTC2), with V3-11 resembling the MHC-E binding motif. MHC restrictions and references provided. (d) In silico epitope predictions for HLA-E binding using the IEDB analysis resource, covering the entire spike sequence. Graphs exhibit HLA-E*01:01 binding scores, proteasomal cleavage,

transport scores, and total scores combining HLA-E binding and processing. Red dots represent spike SP peptides from (c), and S269-277 corresponds to a previously described peptide. (e) Comparison of binding probabilities to HLA-E and HLA-A using NetMHCpan - 4.1, analyzing the entire SARS-CoV-2 spike protein. Multiple nonamers represented as black dots, with dot positions indicating predicted HLA-E binding capacity. Percentile ranks for HLA-E01:01 (y-axis) and HLA-E02:01 (x-axis) are provided. (f) Representative dot plot showcasing NKG2A' and NKG2C' human NK cell responses. (g) Dot plots displaying the percentage of CD107a' NK cells isolated from HC and WTM at ≥ 221 days p.i. after co-culture with K562-E*01 cells loaded with peptides (VL9, HSP60, or V3_11) or no peptides. Light squares indicate wildtype infected convalescent monkeys, while light gray squares represent HC.
**Extended Data Fig. 9 | Identifying HLA-E Binding Potential in SARS-CoV-2 Signal Peptides.** (a) Literature-based scheme summarizing peptide processing via TAP-dependent and TAP-independent pathways. (b) In silico analysis predicting signal peptide presence in spike proteins and their cleavage sites, with SignalP 6.0 software suggesting cleavage by Signal peptidase (SP) and Signal peptide peptidase (SPP). Signal peptides comprise hydrophobic core (h region), polar C-terminal end (c region), and polar N-terminal region (n region). (c) Schematic displaying four overlapping nonamers in the 5' region of SARS-CoV-2 signal peptide (PODTC2), with V3-11 resembling the MHC-E binding motif. MHC restrictions and references provided. (d) In silico epitope predictions for HLA-E binding using the IEDB analysis resource, covering the entire spike sequence. Graphs exhibit HLA-E*01:01 binding scores, proteasomal cleavage,

transport scores, and total scores combining HLA-E binding and processing. Red dots represent spike SP peptides from (c), and S269-277 corresponds to a previously described peptide. (e) Comparison of binding probabilities to HLA-E and HLA-A using NetMHCpan - 4.1, analyzing the entire SARS-CoV-2 spike protein. Multiple nonamers represented as black dots, with dot positions indicating predicted HLA-E binding capacity. Percentile ranks for HLA-E01:01 (y-axis) and HLA-E02:01 (x-axis) are provided. (f) Representative dot plot showcasing NKG2A' and NKG2C' human NK cell responses. (g) Dot plots displaying the percentage of CD107a⁺ NK cells isolated from HC and WTM at ≥ 221 days p.i. after co-culture with K562-E*01 cells loaded with peptides (VL9, HSP60, or V₃₁₁) or no peptides. Light squares indicate wildtype infected convalescent monkeys, while light gray squares represent HC.
<table><caption>Extended Data Table 1 | Baseline characteristics of Cynomolgus macaque monkeys involved in this study</caption><thead><tr><th>Name</th><th>Species</th><th>Sex</th><th>Birth Date</th><th>MHC Haplotype 1</th><th>MHC Haplotype 2</th><th>Strain used for infection</th><th>SARS-CoV-2 infection date</th><th>Age of the animal on the date of the 1st sample (years)</th><th>First sampling time after inoculation for this study (days)</th><th>Treatment during acute SARS-CoV-2 infection</th><th>Reused animal (according to 3 R rule)</th><th>Other previous interventions before this study</th><th>Relapse time between previous intervention and inclusion in this study (months)</th></tr></thead><tbody><tr><td>HC_1</td><td>Cyno</td><td>F</td><td>14.03.2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>3.3</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_2</td><td>Cyno</td><td>F</td><td>22.06.2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>3.07</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_3</td><td>Cyno</td><td>M</td><td>28.09.2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>2.8</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_4</td><td>Cyno</td><td>F</td><td>24.07.2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>2.9</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_5</td><td>Cyno</td><td>M</td><td>13.03.2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>3.3</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_6</td><td>Cyno</td><td>F</td><td>18.06.2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>3.0</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_2</td><td>Cyno</td><td>F</td><td>20.12.2016</td><td>H1</td><td>Rec H4 H1</td><td>hCoV-19-France/IDF0372/2020</td><td>25.03.2020</td><td>4.5</td><td>479</td><td>NO</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_4</td><td>Cyno</td><td>F</td><td>06.01.2017</td><td>Rec H3 H5</td><td>Rec H2 H1</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>4.4</td><td>463</td><td>NO</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>8</td></tr><tr><td>Wuhan_5</td><td>Cyno</td><td>M</td><td>14.02.2017</td><td>H4</td><td>Rec H4 / H5</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>4.3</td><td>463</td><td>NO</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_7</td><td>Cyno</td><td>M</td><td>12.02.2017</td><td>H5</td><td>Rec H1 H5</td><td>hCoV-19-France/IDF0372/2020</td><td>25.03.2020</td><td>4.3</td><td>479</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>8</td></tr><tr><td>Wuhan_15</td><td>Cyno</td><td>M</td><td>13.02.2017</td><td>Rec H3 H5</td><td>Rec H2 H1</td><td>hCoV-19-France/IDF0372/2020</td><td>15.04.2020</td><td>4.2</td><td>461</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_1</td><td>Cyno</td><td>M</td><td>14.02.2017</td><td>H1</td><td>Rec H4 (H2) H1</td><td>hCoV-19-France/IDF0372/2020</td><td>15.04.2020</td><td>4.2</td><td>461</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_3</td><td>Cyno</td><td>F</td><td>22.02.2017</td><td>H4</td><td>H2</td><td>hCoV-19-France/IDF0372/2020</td><td>15.04.2020</td><td>4.3</td><td>461</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_10</td><td>Cyno</td><td>M</td><td>26.02.2017</td><td>H3</td><td>Rec H4 H1</td><td>hCoV-19-France/IDF0372/2020</td><td>15.04.2020</td><td>4.2</td><td>461</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>8</td></tr><tr><td>Wuhan_6</td><td>Cyno</td><td>M</td><td>04.03.2017</td><td>Rec H1 / H2</td><td>H7</td><td>hCoV-19-France/IDF0372/2020</td><td>15.04.2020</td><td>4.1</td><td>461</td><td>NO</td><td>NO</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_9</td><td>Cyno</td><td>F</td><td>13.03.2017</td><td>H5</td><td>H5</td><td>hCoV-19-France/IDF0372/2020</td><td>27.10.2020</td><td>4.1</td><td>221</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_8</td><td>Cyno</td><td>M</td><td>03.03.2017</td><td>H2</td><td>Rec H3 H2</td><td>hCoV-19-France/IDF0372/2020</td><td>27.10.2020</td><td>4.3</td><td>221</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_11</td><td>Cyno</td><td>M</td><td>16.03.2017</td><td>ND</td><td>ND</td><td>hCoV-19-France/IDF0372/2020</td><td>27.10.2020</td><td>4.2</td><td>233</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_12</td><td>Cyno</td><td>F</td><td>03.04.2017</td><td>H3</td><td>Rec H7 H4</td><td>hCoV-19-France/IDF0372/2020</td><td>27.10.2020</td><td>4.1</td><td>190</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_13</td><td>Cyno</td><td>F</td><td>02.01.2016</td><td>H1</td><td>Rec H4 H3</td><td>hCoV-19-France/IDF0372/2020</td><td>27.10.2020</td><td>5.3</td><td>202</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_14</td><td>Cyno</td><td>F</td><td>22.08.2017</td><td>H1</td><td>H1</td><td>hCoV-19-France/IDF0372/2020</td><td>27.10.2020</td><td>3.7</td><td>233</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Osservizi_1</td><td>Cyno</td><td>F</td><td>26.03.2017</td><td>H6</td><td>H2</td><td>SARS-CoV-2</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Osservizi_2</td><td>Cyno</td><td>F</td><td>0.0</td><td>0.0</td><td>0.0</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Osservizi_3</td><td>Cyno</td><td>F</td><td>0.0</td><td>0.0</td><td>0.0</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Osservizi_4</td><td>Cyno</td><td>F</td><td>0.0</td><td>0.0</td><td>0.0</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Osservizi_5</td><td>Cyno</td><td>F</td><td>0.0</td><td>0.0</td><td>0.0</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Osservizi_6</td><td>Cyno</td><td>F</td><td>0.0</td><td>0.0</td><td>0.0</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Osservizi_7</td><td>Cyno</td><td>F</td><td>0.0</td><td>0.0</td><td>0.0</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Osservizi_8</td><td>Cyno</td><td>F</td><td>0.0</td><td>0.0</td><td>0.0</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Osservizi_9</td><td>Cyno</td><td>F</td><td>0.0</td><td>0.0</td><td>0.0</td><td>hCoV-19-France/IDF0372/2020</td><td>16.04.2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr></tbody></table>

For all the animals the date of first sampling used to perform the analysis is indicated. The second sampling occurred 2-8 weeks later depending on the monkeys. NA means not applicable. HC are highlighted in gray, WTM in blue and OM in red.
Extended Data Table 1 | Baseline characteristics of Cynomolgus macaque monkeys involved in this study

<table><thead><tr><th>Name</th><th>Species</th><th>Sex</th><th>Birth Date</th><th>MHC Haplotype 1</th><th>MHC Haplotype 2</th><th>Strain used for infection</th><th>SARS-CoV-2 infection date</th><th>Age of the animal on the date of the 1st sample (years)</th><th>First sampling time after inoculation for this study (days)</th><th>Treatment during acute SARS-CoV-2 infection</th><th>Reused animal (according to 3 R rule)</th><th>Other previous interventions before this study</th><th>Relapse time between previous intervention and inclusion in this study (months)</th></tr></thead><tbody><tr><td>HC_1</td><td>Cyno</td><td>F</td><td>14/03/2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>3.3</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_2</td><td>Cyno</td><td>F</td><td>22/06/2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>3.07</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_3</td><td>Cyno</td><td>M</td><td>28/09/2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>2.8</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_4</td><td>Cyno</td><td>F</td><td>24/07/2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>2.9</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_5</td><td>Cyno</td><td>M</td><td>15/03/2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>3.3</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>HC_6</td><td>Cyno</td><td>F</td><td>18/06/2018</td><td>ND</td><td>ND</td><td>NA</td><td>NA</td><td>3.0</td><td>NA</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_2</td><td>Cyno</td><td>F</td><td>20/12/2016</td><td>H1</td><td>Rec H4 H1</td><td>hCoV-19-France/IDF0372/2020</td><td>25/03/2020</td><td>4.5</td><td>479</td><td>NO</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_4</td><td>Cyno</td><td>F</td><td>06/01/2017</td><td>Rec H3 H5</td><td>Rec H2 H1</td><td>hCoV-19-France/IDF0372/2020</td><td>16/04/2020</td><td>4.4</td><td>463</td><td>NO</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>8</td></tr><tr><td>Wuhan_5</td><td>Cyno</td><td>M</td><td>14/02/2017</td><td>H4</td><td>Rec H4 / H5</td><td>hCoV-19-France/IDF0372/2020</td><td>16/04/2020</td><td>4.3</td><td>463</td><td>NO</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_7</td><td>Cyno</td><td>M</td><td>12/02/17</td><td>H5</td><td>Rec H1 H5</td><td>hCoV-19-France/IDF0372/2020</td><td>25/03/2020</td><td>4.3</td><td>479</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>8</td></tr><tr><td>Wuhan_15</td><td>Cyno</td><td>M</td><td>13/02/2017</td><td>Rec H3 H5</td><td>Rec H2 H1</td><td>hCoV-19-France/IDF0372/2020</td><td>15/04/2020</td><td>4.2</td><td>461</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_1</td><td>Cyno</td><td>M</td><td>14/02/2017</td><td>H1</td><td>Rec H4 (H2) H1</td><td>hCoV-19-France/IDF0372/2020</td><td>15/04/2020</td><td>4.2</td><td>461</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_3</td><td>Cyno</td><td>F</td><td>22/02/2017</td><td>H4</td><td>H2</td><td>hCoV-19-France/IDF0372/2020</td><td>15/04/2020</td><td>4.3</td><td>461</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_10</td><td>Cyno</td><td>M</td><td>26/02/2017</td><td>H3</td><td>Rec H4 H1</td><td>hCoV-19-France/IDF0372/2020</td><td>15/04/2020</td><td>4.2</td><td>461</td><td>YES (Hydroxychloroquine)</td><td>YES</td><td>Non-SARS-CoV-2 related immunisation</td><td>8</td></tr><tr><td>Wuhan_6</td><td>Cyno</td><td>M</td><td>04/03/2017</td><td>Rec H1 / H2</td><td>H7</td><td>hCoV-19-France/IDF0372/2020</td><td>15/04/2020</td><td>4.1</td><td>461</td><td>NO</td><td>NO</td><td>Non-SARS-CoV-2 related immunisation</td><td>?</td></tr><tr><td>Wuhan_9</td><td>Cyno</td><td>F</td><td>13/03/2017</td><td>H5</td><td>H5</td><td>hCoV-19-France/IDF0372/2020</td><td>27/10/2020</td><td>4.1</td><td>221</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_8</td><td>Cyno</td><td>M</td><td>03/03/2017</td><td>H2</td><td>Rec H3 H2</td><td>hCoV-19-France/IDF0372/2020</td><td>27/10/2020</td><td>4.3</td><td>221</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_11</td><td>Cyno</td><td>M</td><td>16/03/2017</td><td>ND</td><td>ND</td><td>hCoV-19-France/IDF0372/2020</td><td>27/10/2020</td><td>4.2</td><td>233</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_12</td><td>Cyno</td><td>F</td><td>03/04/2017</td><td>H3</td><td>Rec H7 H4</td><td>hCoV-19-France/IDF0372/2020</td><td>27/10/2020</td><td>4.1</td><td>190</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_13</td><td>Cyno</td><td>F</td><td>02/01/2016</td><td>H1</td><td>Rec H4 H3</td><td>hCoV-19-France/IDF0372/2020</td><td>27/10/2020</td><td>5.3</td><td>202</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Wuhan_14</td><td>Cyno</td><td>F</td><td>22/08/2017</td><td>H1</td><td>H1</td><td>hCoV-19-France/IDF0372/2020</td><td>27/10/2020</td><td>3.7</td><td>233</td><td>NO</td><td>NO</td><td>NONE</td><td>NA</td></tr><tr><td>Osservizi_1</td><td>Cyno</td><td>F</td><td>26/03/2017</td><td>H6</td><td>H2</td><td>SARS-CoV-2</td><td>16/04/2020</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>0</td><td></td><td></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>0</td><td></td><td></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>0</td><td></td><td></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>0</td><td></td><td></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>0</td><td></td><td></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>0</td><td></td><td></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>0</td><td></td><td></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>0</td><td></td><td></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr></tbody></table>

For all the animals the date of first sampling used to perform the analysis is indicated. The second sampling occurred 2-8 weeks later depending on the monkeys. NA means not applicable. HC are highlighted in gray, WTM in blue and OM in red.
# Reporting Summary

Nature Portfolio wishes to improve the reproducibility of the work that we publish. This form provides structure for consistency and transparency in reporting. For further information on Nature Portfolio policies, see our [Editorial Policies](#) and the [Editorial Policy Checklist](#).

## Statistics

For all statistical analyses, confirm that the following items are present in the figure legend, table legend, main text, or Methods section.

n/a | **Confirmed**

☐ ☑ The exact sample size (n) for each experimental group/condition, given as a discrete number and unit of measurement

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*Give *P* values as exact values whenever suitable.*

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*Our web collection on statistics for biologists contains articles on many of the points above.*

## Software and code

Policy information about [availability of computer code](#)

**Data collection** Flow cytometry analysis was performed using a Fortessa (BD Biosciences) equipped with DIVA software (version 8.0). Immunofluorescence analysis was carried out using either a CELENA® X High Content Imaging System (LOGOS BIOSYSTEMS, South Korea) with the CELENA® X Explorer (version 1.6.0) or a spinning-disk Ti2E Microscope (Nikon - Yokagawa CSU W1). Thermal cycling was conducted in a 7500 real-time PCR system (Applied Biosystems) equipped with Windows 10 and 7500 Fast software version 2.3.

**Data analysis** The experimental group size estimation was performed using G Power software version 3.1.9.7, and fluorescence quantification and cell segmentation were carried out using the Fiji software (version 1.53 with Java 1.8.0_322). In the quest to identify SARS-CoV-2 peptides with the potential for efficient binding to MHC-E, IEBD prediction tools (version 2.27) were employed, and Signalp software (version 6.0) was used for further analysis. Cytometry analysis was conducted with FlowJo software (version 10.4.2, Tree Star, Ashland, OR). Subsequently, data analysis and statistical tests were performed using GraphPad Prism 7 (GraphPad Software, version 10.0.2, San Diego, CA).

For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors and reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Portfolio [guidelines for submitting code & software](#) for further information.
# Reporting Summary

Nature Portfolio wishes to improve the reproducibility of the work that we publish. This form provides structure for consistency and transparency in reporting. For further information on Nature Portfolio policies, see our [Editorial Policies](#) and the [Editorial Policy Checklist](#).

## Statistics

For all statistical analyses, confirm that the following items are present in the figure legend, table legend, main text, or Methods section.

<figure><img src="image_120.png" /></figure>

Our web collection on [statistics for biologists](#) contains articles on many of the points above.

## Software and code

Policy information about [availability of computer code](#)

**Data collection** Flow cytometry analysis was performed using a Fortessa (BD Biosciences) equipped with DIVA software (version 8.0). Immunofluorescence analysis was carried out using either a CELENA® X High Content Imaging System (LOGOS BIOSYSTEMS, South Korea) with the CELENA® X Explorer (version 1.6.0) or a spinning-disk Ti2E Microscope (Nikon - Yokagawa CSU W1). Thermal cycling was conducted in a 7500 real-time PCR system (Applied Biosystems) equipped with Windows 10 and 7500 Fast software version 2.3.

**Data analysis** The experimental group size estimation was performed using G Power software version 3.1.9.7, and fluorescence quantification and cell segmentation were carried out using the Fiji software (version 1.53 with Java 1.8.0_322). In the quest to identify SARS-CoV-2 peptides with the potential for efficient binding to MHC-E, IEBD prediction tools (version 2.27) were employed, and Signalp software (version 6.0) was used for further analysis. Cytometry analysis was conducted with FlowJo software (version 10.4.2, Tree Star, Ashland, OR). Subsequently, data analysis and statistical tests were performed using GraphPad Prism 7 (GraphPad Software, version 10.0.2, San Diego, CA).

For manuscripts utilizing custom algorithms or software that are central to the research but not yet described in published literature, software must be made available to editors and reviewers. We strongly encourage code deposition in a community repository (e.g. GitHub). See the Nature Portfolio [guidelines for submitting code & software](#) for further information.
# Data

Policy information about [availability of data](#)

All manuscripts must include a [data availability statement](#). This statement should provide the following information, where applicable:

- Accession codes, unique identifiers, or web links for publicly available datasets

- A description of any restrictions on data availability

- For clinical datasets or third party data, please ensure that the statement adheres to our [policy](#)

All the data that support the study's findings are included either within the article itself or are provided in a format that readers can access directly from the article. The authors provide raw data files associated with the study. These files likely contain detailed data points and information related to the research. All figures presented in the manuscript are linked to the corresponding raw data files.

All omics data are deposited in public repositories and access codes specified in the paper.

# Field-specific reporting

Please select the one below that is the best fit for your research. If you are not sure, read the appropriate sections before making your selection.

<figure><img src="image_103.png" /></figure>

Life sciences

<figure><img src="image_104.png" /></figure>

Behavioural & social sciences

<figure><img src="image_105.png" /></figure>

Ecological, evolutionary & environmental sciences

For a reference copy of the document with all sections, see [nature.com/documents/nr-reporting-summary-flat.pdf](https://nature.com/documents/nr-reporting-summary-flat.pdf)

# Life sciences study design

All studies must disclose on these points even when the disclosure is negative.

Sample size

We followed the "3Rs" principle for animal research, aiming to minimize the use of experimental subjects. Animals were selected to closely match in terms of age, weight, and genotype. Sample size calculations were performed using power analysis, which accounts for effect size, standard deviation, type 1 error, and 80% power in a two-sample t-test with a 5% significance level (two-sided test). We used G power software version 3.1.9.7. for these calculations, with D determined as (difference in means)/(standard deviation), estimated from our preliminary results. We considered a maximum D value of 1.8 based on previous studies for sample size calculation.

Data exclusions

No data were excluded from the analyses.

Replication

Some assays were performed as replicates: viral quantifications and competitive analysis for binding of the peptides to MHC. The latter comprised three replicates (three independent experiments for each condition). We did not observe any major variation with all the replicates. All results were included in the manuscript. For the other assays, we only used biological replica (ie distinct animals). No other attempts were made at replication due to the limitation in volume of samples, and also duration of the in vivo study (2 years), substantial costs associated with animal acquisition, per diem charges, and surgical costs.

Randomization

Sample collection and analyses were performed in random order.

Blinding

The investigators were not blinded while the animal handlers were blinded to group allocation.

# Reporting for specific materials, systems and methods

We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.

## Materials & experimental systems

<table><thead><tr><th>n/a</th><th>Involved in the study</th></tr></thead><tbody><tr><td>☐</td><td>Antibodies</td></tr><tr><td>☐</td><td>Eukaryotic cell lines</td></tr><tr><td>☒</td><td>Palaeontology and archaeology</td></tr><tr><td>☐</td><td>Animals and other organisms</td></tr><tr><td>☐</td><td>Human research participants</td></tr><tr><td>☒</td><td>Clinical data</td></tr><tr><td>☒</td><td>Dual use research of concern</td></tr></tbody></table>

## Methods

<table><thead><tr><th>n/a</th><th>Involved in the study</th></tr></thead><tbody><tr><td>☒</td><td>ChIP-seq</td></tr><tr><td>☐</td><td>Flow cytometry</td></tr><tr><td>☒</td><td>MRI-based neuroimaging</td></tr></tbody></table>

## Antibodies

Antibodies used

These antibodies, along with their respective characteristics, were crucial for ensuring the accuracy and reliability of our research findings.
# Data

Policy information about [availability of data](#)

All manuscripts must include a [data availability statement](#). This statement should provide the following information, where applicable:

- Accession codes, unique identifiers, or web links for publicly available datasets

- A description of any restrictions on data availability

- For clinical datasets or third party data, please ensure that the statement adheres to our [policy](#)

All the data that support the study's findings are included either within the article itself or are provided in a format that readers can access directly from the article. The authors provide raw data files associated with the study. These files likely contain detailed data points and information related to the research. All figures presented in the manuscript are linked to the corresponding raw data files.

All omics data are deposited in public repositories and access codes specified in the paper.

# Field-specific reporting

Please select the one below that is the best fit for your research. If you are not sure, read the appropriate sections before making your selection.

<figure><img src="image_121.png" /></figure>

Life sciences

<figure><img src="image_122.png" /></figure>

Behavioural & social sciences

<figure><img src="image_123.png" /></figure>

Ecological, evolutionary & environmental sciences

For a reference copy of the document with all sections, see [nature.com/documents/nr-reporting-summary-flat.pdf](https://nature.com/documents/nr-reporting-summary-flat.pdf)

# Life sciences study design

All studies must disclose on these points even when the disclosure is negative.

Sample size

We followed the "3Rs" principle for animal research, aiming to minimize the use of experimental subjects. Animals were selected to closely match in terms of age, weight, and genotype. Sample size calculations were performed using power analysis, which accounts for effect size, standard deviation, type 1 error, and 80% power in a two-sample t-test with a 5% significance level (two-sided test). We used G power software version 3.1.9.7. for these calculations, with D determined as (difference in means)/(standard deviation), estimated from our preliminary results. We considered a maximum D value of 1.8 based on previous studies for sample size calculation.

Data exclusions

No data were excluded from the analyses.

Replication

Some assays were performed as replicates: viral quantifications and competitive analysis for binding of the peptides to MHC. The latter comprised three replicates (three independent experiments for each condition). We did not observe any major variation with all the replicates. All results were included in the manuscript. For the other assays, we only used biological replica (ie distinct animals). No other attempts were made at replication due to the limitation in volume of samples, and also duration of the in vivo study (2 years), substantial costs associated with animal acquisition, per diem charges, and surgical costs.

Randomization

Sample collection and analyses were performed in random order.

Blinding

The investigators were not blinded while the animal handlers were blinded to group allocation.

# Reporting for specific materials, systems and methods

We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.

## Materials & experimental systems

<table><thead><tr><th>n/a</th><th>Involved in the study</th></tr></thead><tbody><tr><td>☐</td><td>Antibodies</td></tr><tr><td>☐</td><td>Eukaryotic cell lines</td></tr><tr><td>☒</td><td>Palaeontology and archaeology</td></tr><tr><td>☐</td><td>Animals and other organisms</td></tr><tr><td>☐</td><td>Human research participants</td></tr><tr><td>☒</td><td>Clinical data</td></tr><tr><td>☒</td><td>Dual use research of concern</td></tr></tbody></table>

## Methods

<table><thead><tr><th>n/a</th><th>Involved in the study</th></tr></thead><tbody><tr><td>☒</td><td>ChIP-seq</td></tr><tr><td>☐</td><td>Flow cytometry</td></tr><tr><td>☒</td><td>MRI-based neuroimaging</td></tr></tbody></table>

## Antibodies

Antibodies used

These antibodies, along with their respective characteristics, were crucial for ensuring the accuracy and reliability of our research findings.
CD45, labeled with BUV395 and provided by BD Biosciences (Clone: D058-1283, Isotype: IgG1, k, Reference: 564099), was used at a dilution of 1/30. Control conditions included Isotype + FMO and Providers + NHP reagent. CD4, labeled with PerCp-Cy5 and sourced from BD Biosciences (Clone: L200, Isotype: IgG1, k, Reference: 552838), was utilized at a dilution of 1/15. Control conditions comprised Isotype + FMO and Providers + NHP reagent.
CD336 (NKp44), labeled with PC7 and obtained from Miltenyi Biotec (Clone: REA1163, Isotype: IgG1, Reference: 130-120-359), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD337 (NKp30), labeled with APC and sourced from Miltenyi Biotec (Clone: REA823, Isotype: IgG1, Reference: 130-112-431), was employed at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD107a, labeled with A700 and provided by BD Biosciences (Clone: H4A3, Isotype: IgG1, k, Reference: 561340), was used at a dilution of 1/10. Control conditions included Isotype + FMO and Providers + NHP reagent. NKp80, labeled with APC Vio® 770 and sourced from Miltenyi Biotec (Clone: REA845, Isotype: IgG1, Reference: 130-112-593), was utilized at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD226, labeled with BV605 and obtained from BD Biosciences (Clone: DX11, Isotype: IgG1, k, Reference: 742495), was used at a dilution of 1/15. Control conditions included Isotype + FMO and Providers + NHP reagent. CD20, labeled with BV711 and provided by BD Biosciences (Clone: 2H7, Isotype: IgG2b, k, Reference: 563126), was employed at a dilution of 1/30. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD103, labeled with BV650 and sourced from BD Biosciences (Clone: Ber-ACT8, Isotype: IgG1, k, Reference: 743653), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. KI-67, labeled with AF®488 and obtained from BD Biosciences (Clone: B56, Isotype: IgG1, k, Reference: 561165), was utilized at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. GZMB, labeled with V450 and provided by BD Biosciences (Clone: GB11, Isotype: IgG1, Reference: 561151), was used at a dilution of 1/15. Control conditions included Isotype + FMO and Providers + NHP reagent. IFN-γ, labeled with BV510 and sourced from BD Biosciences (Clone: B27, Isotype: IgG1, k, Reference: 563287), was employed at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. IL-17, labeled with BV786 and obtained from BioLegend (Clone: BL168, Isotype: IgG1, Reference: 512337), was utilized at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD4, labeled with PE-Cy™7 and sourced from BD Biosciences (Clone: L200, Isotype: IgG1, k, Reference: 560644), was used at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD8, labeled with VioBlue® and obtained from Miltenyi Biotec (Clone: Bw135/80, Isotype: IgG2ak, Reference: 130-113-162), was employed at a dilution of 1/30. Control conditions included Isotype + FMO and Providers + NHP reagent. CD7, labeled with BV650 and provided by BD Biosciences (Clone: M-T701, Isotype: IgG1, k, Reference: 740565), was used at a dilution of 1/15. Control conditions comprised Isotype + FMO and Providers + NHP reagent. HLA-DR, labeled with AF®700 and sourced from BD Biosciences (Clone: L243 (G46-6), Isotype: IgG2a, k, Reference: 560743), was utilized at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD20, labeled with BV711 and obtained from BD Biosciences (Clone: 2H7, Isotype: IgG2b, k, Reference: 563126), was employed at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD45RA, labeled with BV786 and sourced from BD Biosciences (Clone: 5H9, Isotype: IgG1, k, Reference: 741010), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD34, labeled with BUV737 and provided by BD Biosciences (Clone: 563, Isotype: IgG1, k, Reference: 741868), was utilized at a dilution of 1/15. Control conditions comprised Isotype + FMO and Providers + NHP reagent. EOMES, labeled with FITC and sourced from Invitrogen (Clone: WD1928, Isotype: IgG1, k, Reference: 11-4877-42), was used at a dilution of 1/30. Control conditions included Isotype + FMO and Providers + NHP reagent. T-bet, labeled with PerCP/Cy5.5 and obtained from SONY (Clone: 4B10, Isotype: IgG1, k, Reference: RT3824030), was employed at a dilution of 1/10. Control conditions comprised Isotype + FMO and Providers + NHP reagent. IL-21, labeled with AF®647 and provided by BD Biosciences (Clone: 3A3-N2.1, Isotype: IgG1, Reference: 562043), was used at a dilution of 1/40. Control conditions included Isotype + FMO and Providers + NHP reagent. IFN-γ, labeled with APC/Cy7 and sourced from SONY (Clone: B27, Isotype: IgG1, k, Reference: RT3132620), was employed at a dilution of 1/15. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD20, labeled with A700 and obtained from BD Biosciences (Clone: 2H7, Isotype: IgG2b, k, Reference: 560631), was used at a dilution of 1/30. Control conditions included Isotype + FMO and Providers + NHP reagent. CD34, labeled with BUV737 and provided by BD Biosciences (Clone: 563, Isotype: IgG1, k, Reference: 741868), was utilized at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD45RA, labeled with BV786 and sourced from BD Biosciences (Clone: 5H9, Isotype: IgG1, k, Reference: 741010), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CCR7, labeled with APC/Cy7 and sourced from BioLegend (Clone: G043H7, Isotype: IgG2a, k, Reference: 353211), was utilized at a dilution of 1/15. Control conditions included Isotype + FMO and Providers + NHP reagent. CXCR3 (CD183), labeled with PE-Cy™7 and obtained from BD Biosciences (Clone: 1C6, Isotype: IgG1, k, Reference: 560831), was employed at a dilution of 1/30. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD44, labeled with BUV661 and provided by BD Biosciences (Clone: G44-26, Isotype: IgG2b, k, Reference: 741615), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD127, labeled with PE-Cy5 and sourced from Invitrogen (Clone: eBioRDR5, Isotype: IgG1, k, Reference: 15-1278-42), was employed at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. GATA-3, labeled with BV421/450 and obtained from BD Biosciences (Clone: L50-823, Isotype: IgG1, k, Reference: 563349), was utilized at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent.

T-bet, labeled with PerCP/Cy5.5 and sourced from SONY (Clone: 4B10, Isotype: IgG1, k, Reference: RT3824030), was used at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD14, labeled with Alexa 488, FITC, and BB515, was obtained from Miltenyi Biotec (Clone: TÜK4, Isotype: IgG2ak, Reference: 130-113-146). It was used at a dilution of 1/10, and control conditions included Isotype + FMO and Providers + NHP reagent. MHC-E, labeled with PE and provided by NOVUS (Clone: 3D12MHLA-E, Isotype: IgG1, k, Reference: NBP2-00277), was used at a dilution of 1/30. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD206, labeled with ECD and sourced from BD Biosciences (Clone: 19.2, Isotype: IgG1), was employed in our analysis. Control conditions included Isotype + FMO and Providers + NHP reagent. IL-10, labeled with PC7 and obtained from BioLegend (Clone: JES3-9D7, Isotype: IgG1, k, Reference: 501419), was utilized in our experiments. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD64, labeled with APC and provided by BD Biosciences (Clone: 10,1, Isotype: IgG2b, k, Reference: 561189), was used in our analysis. Control conditions included Isotype + FMO and Providers + NHP reagent. CD11C, labeled with BV605 and sourced from BD Biosciences (Clone: S-HCL-3, Isotype: IgG2b, k, Reference: 744436), was employed in our experiments. Control conditions comprised Isotype + FMO and Providers + NHP reagent. NKG2c, labeled with Vio® Bright R720 and obtained from Miltenyi Biotec (Clone: REA205, Isotype: IgG2b, k, Reference: 130-130-663), was utilized in our analysis. Control conditions included Isotype + FMO and Providers + NHP reagent. CD163, labeled with BV421/450 and provided by BioLegend (Clone: GHI/61, Isotype: IgG1), was used in our experiments. Control conditions comprised Isotype + FMO and Providers + NHP reagent.

Validation

the antibodies employed for flow cytometry analysis underwent a thorough validation process to ensure their reliability and accuracy in detecting specific immune cell populations and markers. The validation process included several critical steps:

**Antibody Selection:** The initial step in the validation process involved the careful selection of antibodies. Antibodies were chosen
CD45, labeled with BUV395 and provided by BD Biosciences (Clone: D058-1283, Isotype: IgG1, k, Reference: 564099), was used at a dilution of 1/30. Control conditions included Isotype + FMO and Providers + NHP reagent. CD4, labeled with PerCp-Cy5 and sourced from BD Biosciences (Clone: L200, Isotype: IgG1, k, Reference: 552838), was utilized at a dilution of 1/15. Control conditions comprised Isotype + FMO and Providers + NHP reagent.
CD336 (NKp44), labeled with PC7 and obtained from Miltenyi Biotec (Clone: REA1163, Isotype: IgG1, Reference: 130-120-359), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD337 (NKp30), labeled with APC and sourced from Miltenyi Biotec (Clone: REA823, Isotype: IgG1, Reference: 130-112-431), was employed at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD107a, labeled with A700 and provided by BD Biosciences (Clone: H4A3, Isotype: IgG1, k, Reference: 561340), was used at a dilution of 1/10. Control conditions included Isotype + FMO and Providers + NHP reagent. NKp80, labeled with APC Vio® 770 and sourced from Miltenyi Biotec (Clone: REA845, Isotype: IgG1, Reference: 130-112-593), was utilized at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD226, labeled with BV605 and obtained from BD Biosciences (Clone: DX11, Isotype: IgG1, k, Reference: 742495), was used at a dilution of 1/15. Control conditions included Isotype + FMO and Providers + NHP reagent. CD20, labeled with BV711 and provided by BD Biosciences (Clone: 2H7, Isotype: IgG2b, k, Reference: 563126), was employed at a dilution of 1/30. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD103, labeled with BV650 and sourced from BD Biosciences (Clone: Ber-ACT8, Isotype: IgG1, k, Reference: 743653), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. KI-67, labeled with AF®488 and obtained from BD Biosciences (Clone: B56, Isotype: IgG1, k, Reference: 561165), was utilized at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. GZMB, labeled with V450 and provided by BD Biosciences (Clone: GB11, Isotype: IgG1, Reference: 561151), was used at a dilution of 1/15. Control conditions included Isotype + FMO and Providers + NHP reagent. IFN-γ, labeled with BV510 and sourced from BD Biosciences (Clone: B27, Isotype: IgG1, k, Reference: 563287), was employed at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. IL-17, labeled with BV786 and obtained from BioLegend (Clone: BL168, Isotype: IgG1, Reference: 512337), was utilized at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD4, labeled with PE-Cy™7 and sourced from BD Biosciences (Clone: L200, Isotype: IgG1, k, Reference: 560644), was used at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD8, labeled with VioBlue® and obtained from Miltenyi Biotec (Clone: Bw135/80, Isotype: IgG2ak, Reference: 130-113-162), was employed at a dilution of 1/30. Control conditions included Isotype + FMO and Providers + NHP reagent. CD7, labeled with BV650 and provided by BD Biosciences (Clone: M-T701, Isotype: IgG1, k, Reference: 740565), was used at a dilution of 1/15. Control conditions comprised Isotype + FMO and Providers + NHP reagent. HLA-DR, labeled with AF®700 and sourced from BD Biosciences (Clone: L243 (G46-6), Isotype: IgG2a, k, Reference: 560743), was utilized at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD20, labeled with BV711 and obtained from BD Biosciences (Clone: 2H7, Isotype: IgG2b, k, Reference: 563126), was employed at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD45RA, labeled with BV786 and sourced from BD Biosciences (Clone: 5H9, Isotype: IgG1, k, Reference: 741010), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD34, labeled with BUV737 and provided by BD Biosciences (Clone: 563, Isotype: IgG1, k, Reference: 741868), was utilized at a dilution of 1/15. Control conditions comprised Isotype + FMO and Providers + NHP reagent. EOMES, labeled with FITC and sourced from Invitrogen (Clone: WD1928, Isotype: IgG1, k, Reference: 11-4877-42), was used at a dilution of 1/30. Control conditions included Isotype + FMO and Providers + NHP reagent. T-bet, labeled with PerCP/Cy5.5 and obtained from SONY (Clone: 4B10, Isotype: IgG1, k, Reference: RT3824030), was employed at a dilution of 1/10. Control conditions comprised Isotype + FMO and Providers + NHP reagent. IL-21, labeled with AF®647 and provided by BD Biosciences (Clone: 3A3-N2.1, Isotype: IgG1, Reference: 562043), was used at a dilution of 1/40. Control conditions included Isotype + FMO and Providers + NHP reagent. IFN-γ, labeled with APC/Cy7 and sourced from SONY (Clone: B27, Isotype: IgG1, k, Reference: RT3132620), was employed at a dilution of 1/15. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD20, labeled with A700 and obtained from BD Biosciences (Clone: 2H7, Isotype: IgG2b, k, Reference: 560631), was used at a dilution of 1/30. Control conditions included Isotype + FMO and Providers + NHP reagent. CD34, labeled with BUV737 and provided by BD Biosciences (Clone: 563, Isotype: IgG1, k, Reference: 741868), was utilized at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD45RA, labeled with BV786 and sourced from BD Biosciences (Clone: 5H9, Isotype: IgG1, k, Reference: 741010), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CCR7, labeled with APC/Cy7 and sourced from BioLegend (Clone: G043H7, Isotype: IgG2a, k, Reference: 353211), was utilized at a dilution of 1/15. Control conditions included Isotype + FMO and Providers + NHP reagent. CXCR3 (CD183), labeled with PE-Cy™7 and obtained from BD Biosciences (Clone: 1C6, Isotype: IgG1, k, Reference: 560831), was employed at a dilution of 1/30. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD44, labeled with BUV661 and provided by BD Biosciences (Clone: G44-26, Isotype: IgG2b, k, Reference: 741615), was used at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent. CD127, labeled with PE-Cy5 and sourced from Invitrogen (Clone: eBioRDR5, Isotype: IgG1, k, Reference: 15-1278-42), was employed at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. GATA-3, labeled with BV421/450 and obtained from BD Biosciences (Clone: L50-823, Isotype: IgG1, k, Reference: 563349), was utilized at a dilution of 1/20. Control conditions included Isotype + FMO and Providers + NHP reagent.

T-bet, labeled with PerCP/Cy5.5 and sourced from SONY (Clone: 4B10, Isotype: IgG1, k, Reference: RT3824030), was used at a dilution of 1/20. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD14, labeled with Alexa 488, FITC, and BB515, was obtained from Miltenyi Biotec (Clone: TÜK4, Isotype: IgG2ak, Reference: 130-113-146). It was used at a dilution of 1/10, and control conditions included Isotype + FMO and Providers + NHP reagent. MHC-E, labeled with PE and provided by NOVUS (Clone: 3D12MHL-A, Isotype: IgG1, k, Reference: NBP2-00277), was used at a dilution of 1/30. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD206, labeled with ECD and sourced from BD Biosciences (Clone: 19.2, Isotype: IgG1), was employed in our analysis. Control conditions included Isotype + FMO and Providers + NHP reagent. IL-10, labeled with PC7 and obtained from BioLegend (Clone: JES3-9D7, Isotype: IgG1, k, Reference: 501419), was utilized in our experiments. Control conditions comprised Isotype + FMO and Providers + NHP reagent. CD64, labeled with APC and provided by BD Biosciences (Clone: 10,1, Isotype: IgG2b, k, Reference: 561189), was used in our analysis. Control conditions included Isotype + FMO and Providers + NHP reagent. CD11C, labeled with BV605 and sourced from BD Biosciences (Clone: S-HCL-3, Isotype: IgG2b, k, Reference: 744436), was employed in our experiments. Control conditions comprised Isotype + FMO and Providers + NHP reagent. NKG2c, labeled with Vio® Bright R720 and obtained from Miltenyi Biotec (Clone: REA205, Isotype: IgG2b, k, Reference: 130-130-663), was utilized in our analysis. Control conditions included Isotype + FMO and Providers + NHP reagent. CD163, labeled with BV421/450 and provided by BioLegend (Clone: GHI/61, Isotype: IgG1), was used in our experiments. Control conditions comprised Isotype + FMO and Providers + NHP reagent.

Validation

the antibodies employed for flow cytometry analysis underwent a thorough validation process to ensure their reliability and accuracy in detecting specific immune cell populations and markers. The validation process included several critical steps:

**Antibody Selection:** The initial step in the validation process involved the careful selection of antibodies. Antibodies were chosen
based on their known specificity for the target antigens of interest. Extensive literature review and consultation with experts in the field were conducted to confirm their suitability for our study.

**Manufacturer's Specifications:** We reviewed the manufacturer's specifications and technical data sheets for each antibody. This information included details such as clone names, isotypes, recommended dilutions, and references. Understanding these specifications was essential for proper antibody usage.

**Positive and Negative Controls:** To validate antibody performance, we used positive and negative controls. Positive controls included cells or tissues known to express the target antigen, while negative controls were cells or tissues lacking the antigen. These controls helped confirm the specificity of the antibodies.

**Fluorescence Minus One (FMO) Controls:** FMO controls were utilized to assess background fluorescence and determine the true signal from the target antigen. FMO controls included all fluorochromes except the one specific to the tested antibody, allowing us to differentiate specific staining from non-specific background fluorescence.

**Non-Human Primate (NHP) Reagent Controls:** Since our study involved non-human primates, NHP reagent controls were used to ensure the compatibility and specificity of the antibodies in the primate model. These controls helped verify that the antibodies effectively bound to the target antigens in our experimental system.

**Dilution Optimization:** Antibody dilutions were optimized to achieve the best signal-to-noise ratio. Serial dilutions of each antibody were tested to determine the optimal concentration for accurate and robust staining.

## Eukaryotic cell lines

### Policy information about cell lines

**Cell line source(s)**

K562 cell line was provided by the ATCC; The K-562 cell line was purchased from ATCC and transduced with a lentivirus expression vector for human HLA-E was purchased from Applied Biological Materials Inc.

**Authentication**

None of the cell lines were authenticated.

**Mycoplasma contamination**

We confirm that the cell line was tested negative for mycoplasma

**Commonly misidentified lines**
(See JCLAC register)

ATCC® Number: CCL-243™; no commonly misidentified cell lines were used in the study.

## Animals and other organisms

### Policy information about studies involving animals; ARRIVE guidelines recommended for reporting animal research

**Laboratory animals**

Cynomolgus macaques (M. fascicularis) aged 37–60 months were sourced from Mauritian AAALAC-certified breeding centers. The study was conducted at IDMIT infrastructure facilities with appropriate containment levels in accordance with regulations. At the time of infection, all animals were seronegative for specific viruses. Following infection, the macaques were housed individually in biosafety facilities. Both male and female monkeys were included in the study, and sample collection was performed randomly

**Wild animals**

Study did not involve wild animals.

**Field-collected samples**

Study did not involve field-collected samples

**Ethics oversight**

The study protocols received approval from the institutional ethical committee, 'Comité d'Ethique en Expérimentation Animale du Commissariat à l'Energie Atomique et aux Energies Alternatives' (CETEA 44), under statement numbers A20_011, 20_066, and 21_069. Authorization for the study was granted by the 'Research, Innovation, and Education Ministry' under registration numbers APAFIS#24434-2020030216532863v1, APAFIS#29191-2021011811505374 v1, and APAFIS#33414-2021101115102064 v1.

Note that full information on the approval of the study protocol must also be provided in the manuscript.

## Human research participants

### Policy information about studies involving human research participants

**Population characteristics**

Blood samples were collected based on voluntary. To be allowed to give blood sample, Volunteers should had between 18 and 70 years old, and weigh more than 50 kg. Exact age, sexe and ethnic origin of the participantes is not known. Fifty milliliter blood samples were obtained from twelve donors.

**Recruitment**

Blood samples were collected based on voluntary. All blood samples were collected before 2019 and PBMC were isolated using Ficoll gradient and immediately frozen.

**Ethics oversight**

Blood samples from healthy donors were obtained from the French blood bank (Etablissement Français du Sang) as part of an agreement with the Institut Pasteur (CPSL UNT, number 15/EFS/023). The study was approved by the Ethics Review Committee (Comité de protection des personnes) of Île-de-France VII.

Note that full information on the approval of the study protocol must also be provided in the manuscript.
based on their known specificity for the target antigens of interest. Extensive literature review and consultation with experts in the field were conducted to confirm their suitability for our study.

**Manufacturer's Specifications:** We reviewed the manufacturer's specifications and technical data sheets for each antibody. This information included details such as clone names, isotypes, recommended dilutions, and references. Understanding these specifications was essential for proper antibody usage.

**Positive and Negative Controls:** To validate antibody performance, we used positive and negative controls. Positive controls included cells or tissues known to express the target antigen, while negative controls were cells or tissues lacking the antigen. These controls helped confirm the specificity of the antibodies.

**Fluorescence Minus One (FMO) Controls:** FMO controls were utilized to assess background fluorescence and determine the true signal from the target antigen. FMO controls included all fluorochromes except the one specific to the tested antibody, allowing us to differentiate specific staining from non-specific background fluorescence.

**Non-Human Primate (NHP) Reagent Controls:** Since our study involved non-human primates, NHP reagent controls were used to ensure the compatibility and specificity of the antibodies in the primate model. These controls helped verify that the antibodies effectively bound to the target antigens in our experimental system.

**Dilution Optimization:** Antibody dilutions were optimized to achieve the best signal-to-noise ratio. Serial dilutions of each antibody were tested to determine the optimal concentration for accurate and robust staining.

## Eukaryotic cell lines

### Policy information about cell lines

**Cell line source(s)**

K562 cell line was provided by the ATCC; The K-562 cell line was purchased from ATCC and transduced with a lentivirus expression vector for human HLA-E was purchased from Applied Biological Materials Inc.

**Authentication**

None of the cell lines were authenticated.

**Mycoplasma contamination**

We confirm that the cell line was tested negative for mycoplasma

**Commonly misidentified lines**
(See [ICLAC](#) register)

ATCC® Number: CCL-243™; no commonly misidentified cell lines were used in the study.

## Animals and other organisms

### Policy information about studies involving animals; ARRIVE guidelines recommended for reporting animal research

**Laboratory animals**

Cynomolgus macaques (M. fascicularis) aged 37-60 months were sourced from Mauritian AAALAC-certified breeding centers. The study was conducted at IDMIT infrastructure facilities with appropriate containment levels in accordance with regulations. At the time of infection, all animals were seronegative for specific viruses. Following infection, the macaques were housed individually in biosafety facilities. Both male and female monkeys were included in the study, and sample collection was performed randomly

**Wild animals**

Study did not involve wild animals.

**Field-collected samples**

Study did not involve field-collected samples

**Ethics oversight**

The study protocols received approval from the institutional ethical committee, 'Comité d'Ethique en Expérimentation Animale du Commissariat à l'Energie Atomique et aux Energies Alternatives' (CETEA 44), under statement numbers A20_011, 20_066, and 21_069. Authorization for the study was granted by the 'Research, Innovation, and Education Ministry' under registration numbers APAFIS#24434-2020030216532863v1, APAFIS#29191-2021011811505374 v1, and APAFIS#33414-2021101115102064 v1.

Note that full information on the approval of the study protocol must also be provided in the manuscript.

## Human research participants

### Policy information about studies involving human research participants

**Population characteristics**

Blood samples was collected based on voluntary. To be allowed to give blood sample, Volunteers should had between 18 and 70 years old, and weigh more than 50 kg. Exact age, sexe and ethnic origin of the participantes is not known. Fifty milliliter blood samples were obtained from twelve donors.

**Recruitment**

Blood samples was collected based on voluntary. All blood samples were collected before 2019 and PBMC were isolated using Ficoll gradient and immediately frozen.

**Ethics oversight**

Blood samples from healthy donors were obtained from the French blood bank (Etablissement Français du Sang) as part of an agreement with the Institut Pasteur (CPSL UNT, number 15/EFS/023). The study was approved by the Ethics Review Committee (Comité de protection des personnes) of Île-de-France VII.

Note that full information on the approval of the study protocol must also be provided in the manuscript.
# Flow Cytometry

## Plots

Confirm that:

<figure><img src="image_106.png" /></figure>

* The axis labels state the marker and fluorochrome used (e.g. CD4-FITC).

<figure><img src="image_107.png" /></figure>

* The axis scales are clearly visible. Include numbers along axes only for bottom left plot of group (a 'group' is an analysis of identical markers).

<figure><img src="image_108.png" /></figure>

* All plots are contour plots with outliers or pseudocolor plots.

<figure><img src="image_109.png" /></figure>

* A numerical value for number of cells or percentage (with statistics) is provided.

## Methodology

**Sample preparation**

Whole venous blood was collected in ethylenediaminetetraacetic acid (EDTA) tubes. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density-gradient centrifugation. Broncho alveolar lavage fluid have been collected when blood puncture was done. The cell suspension was subsequently filtered through 100- and 40-µm cell strainers, and cells were washed with cold phosphate-buffered saline (PBS). Cells were either immediately stained for flow cytometry or cryopreserved in 90% foetal bovine serum (FBS) and 10% dimethyl sulfphoxide (DMSO) and stored in liquid nitrogen before use. Intracellular staining was performed using BD Cytofix/Cytoperm™.

**Instrument**

Flow cytometry acquisitions were done on a LSRFortessa (BD Biosciences).

**Software**

The data were analysed using Diva (software version 6.1.3, build 2009 05 13 13 29). The data were further analyzed using FlowJo (10.4.2 software, LLC, Ashland, OR, USA). Multiparametric analyses were performed using SPICE (version 5.1). t-SNE was performed with the cytobank (Cytobank, Inc.), using 2,000 iterations and a perplexity of 60.

**Cell population abundance**

Online methods, paragraph: Polychromatic flow cytometry; Cell sorting of NK cell sub-populations.

**Gating strategy**

all gating strategies are provided in extended figures

<figure><img src="image_110.png" /></figure>

Tick this box to confirm that a figure exemplifying the gating strategy is provided in the Supplementary Information.
# Flow Cytometry

## Plots

Confirm that:

<figure><img src="image_124.png" /></figure>

The axis labels state the marker and fluorochrome used (e.g. CD4-FITC).

<figure><img src="image_125.png" /></figure>

The axis scales are clearly visible. Include numbers along axes only for bottom left plot of group (a 'group' is an analysis of identical markers).

<figure><img src="image_126.png" /></figure>

All plots are contour plots with outliers or pseudocolor plots.

<figure><img src="image_127.png" /></figure>

A numerical value for number of cells or percentage (with statistics) is provided.

## Methodology

**Sample preparation**

Whole venous blood was collected in ethylenediaminetetraacetic acid (EDTA) tubes. Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density-gradient centrifugation. Broncho alveolar lavage fluid have been collected when blood puncture was done. The cell suspension was subsequently filtered through 100- and 40-µm cell strainers, and cells were washed with cold phosphate-buffered saline (PBS). Cells were either immediately stained for flow cytometry or cryopreserved in 90% foetal bovine serum (FBS) and 10% dimethyl sulfphoxide (DMSO) and stored in liquid nitrogen before use. Intracellular staining was performed using BD Cytofix/Cytoperm™.

**Instrument**

Flow cytometry acquisitions were done on a LSRFortessa (BD Biosciences).

**Software**

The data were analysed using Diva (software version 6.1.3, build 2009 05 13 13 29). The data were further analyzed using FlowJo (10.4.2 software, LLC, Ashland, OR, USA). Multiparametric analyses were performed using SPICE (version 5.1). t-SNE was performed with the cytobank (Cytobank, Inc.), using 2,000 iterations and a perplexity of 60.

**Cell population abundance**

Online methods, paragraph: Polychromatic flow cytometry; Cell sorting of NK cell sub-populations.

**Gating strategy**

all gating strategies are provided in extended figures

<figure><img src="image_128.png" /></figure>

Tick this box to confirm that a figure exemplifying the gating strategy is provided in the Supplementary Information.