COVID-19 displays remarkable disparity of clinical symptoms, ranging from asymptomatic or 57 mild disease frequently observed in children and younger adults to severe clinical symptoms 58 associated with high mortality mainly in elderly and high-risk patients. These different 59 pathologies are likely to be the result of differences in the immune response to SARS-CoV-2. 
Several studies show that a significant fraction of un-exposed donors possess SARS-CoV-2- donors was verified by SARS-CoV-2 PCR and/ or serology testing (Table S1 , S2).
The response of COVID-19 patients was mainly directed against three proteins, spike, 123 membrane and nucleocapsid, as previously reported , as well as to lower 124 extent and with more variability between donors against ORF3a, ORF9b, NS6, NS7a and 125 NS8 ( Figure 1A 
UMAP cluster analysis revealed five clusters with a distinct transcriptional profile (Figure 2A ).
These were assigned as T follicular-helper-like (Tfh-like, key marker genes IL21, POU2AF1), 7 ( Figure 2B ). Similar clusters have recently been described in SARS-CoV-2-specific T cells 150 (Meckiff et al., 2020) . Especially Tfh-like, transitional and central memory T cells showed a   151   related profile with variable gene expression of IFNG, CSF2, IL21, IL2 and PDCD1 (Figures   152 2B, Figure S2A , B). We also observed three robust clusters (cytotoxic /Th1, type-I interferon, 153 and cycling) indicative of cellular activation and an anti-viral type-I interferon response.
Similar clusters were also identified in SARS-CoV-2 reactive memory T cells from unexposed 155 individuals and we were not able to clearly separate unexposed donors from COVID-19 156 patients or between patients with different disease severity only based on qualitative 157 differences of the reactive T cells ( Figure 2C , Figure S2B ).
Increased expression of the acute and chronic activation markers Ki-67 and CD38, was 159 confirmed by flow-cytometry ( Figure 2D , Figure S3A ) and declined with time after infection 160 ( Figure 2E ), in contrast to the frequencies of reactive T cells ( Figure S3B ). Relative, but 161 especially absolute levels of inflammatory cytokines were increased in COVID-19, such as 162 IL-2, IFN-γ and IL-21, compared to unexposed individuals ( Figure S3C ,D). We also observed 163 a slightly higher production of IL-10. While inflammatory cytokines increased with time after 164 infection, IL-10 was mainly produced during active disease ( Figure S3E ). This finding 165 suggests a counter-regulatory mechanism during acute infection. We observed no 166 differences in the cytokine response or phenotype between the individual SARS-CoV-2 167 proteins ( Figure S4 ).
Taken together, COVID-19 patients generated a pro-inflammatory Th1/cytotoxic-like and Tfh-169 like response against SARS-CoV-2 spike, membrane, and nucleocapsid proteins. However, 170 the differences between patients and unexposed individuals were mainly quantitative rather 171 than qualitative. This suggests that the identified cell clusters are not unique to COVID-19 but 172 may represent a common cellular phenotype of anti-viral T cells.
Recent studies show pre-existing T cell immunity against SARS-CoV-2 in 20-81% of 
Variable cross-reactivity is reported against homologuous epitopes from common cold 
In summary, these data show that antigen-reactive T cells against newly encountered 214 antigens, such as SARS-CoV-2 are present within a natural memory T cell repertoire, most 215 likely due to TCR intrinsic cross-reactivity, as previously described (Bacher et 
CCCoV spike-reactive T cells showed higher production of the inflammatory cytokines IFN-γ,
TNF-α, IL-2 and IL-21 compared to SARS-CoV-2 spike-reactive T cells from unexposed 235 individuals ( Figure 4G , H, Figure S4 ).
In summary, these data show that robust memory CD4+ T cell responses to all four common 
We next compared the response quality of patients with mild (non-hospitalized) versus 274 severe (hospitalized) disease. Classification was based on WHO criteria, whereby WHO 275 groups 3-5 (moderate) and 6-7 (severe) were combined to increase statistical power (see 276   Table S1 ). We found higher frequencies of reactive T cells against the single and pooled 277 SARS-CoV-2 proteins with increasing disease severity ( Figure 6A ). No such correlation was 278 observed for Influenza A as control antigen. The increased frequencies in severe disease 279 were not due to an age bias as shown for a selected group of donors in the age range of 50-280 65 years ( Figure 6B , C, Figure S7 ). However, hospitalized versus non-hospitalized patients 281 within the same age group showed an increased proportion of memory cells within the CD4+
T cell compartment ( Figure 6D ). We next compared TCR avidities and clonalities of SARS- Figure 6I ). This was not significant due to one outlier (grey dot in Figure 6G 
In summary, our data reveal that severe COVID-19 patients showed a strong but rather 303 unfocused CD4+ T cell response. This was characterized by low avidity T cells originating 304 from a rather polyclonal repertoire. Severe disease was also associated with an enlarged 305 total CD4+ memory compartment. However, we do not know the patients pre-infection status 
We found that patients with severe COVID-19 harbored low avidity CD4+ T cells, which were based on WHO criteria, whereby WHO groups 3-5 (moderate) and 6-7 (severe) were 639 combined to increase statistical power (see Table S1 ). Unexposed donors n=50, non- Table S1 and S2 for further details). 51 of 56 COVID-19 patients were tested containing more than 1 TCR alpha and 1 TCR beta (ii) containing more than 1 TCR alpha 806 and no TCR beta sequence (iii) containing more than 1 TCR beta and no TCR alpha 807 sequence (iv) containing more than 2 TCR alpha or more than 2 TCR beta sequences.
Alpha diversity measures were calculated for each patient either for the whole repertoire or 809 divided based on Seurat clusters. R packages "vegan" and "tcR" were used to calculate the Bacher et al. identify excessive but low avidity T cell responses to SARS-CoV-2 as a hallmark of severe but not mild COVID-19. Pre-existing memory to SARS-CoV-2 in unexposed donors also displayed low avidity and harbored multiple, highly variable crossreactivities that were not restricted to common cold coronaviruses. 