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# Human Immune Responses to Epstein-Barr Virus Highlighted by Immunodeficiencies

Sylvain Latour

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Sylvain Latour. Human Immune Responses to Epstein-Barr Virus Highlighted by Immunodeficiencies. Annual Review of Immunology, 2025, 43 (1), pp.723-749. 10.1146/annurev-immunol-082323-035455. hal-05390862

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*Annual Review of Immunology*

# Human Immune Responses to Epstein-Barr Virus Highlighted by Immunodeficiencies

Sylvain Latour<fnref n="1" />,<fnref n="2" />

Annu. Rev. Immunol. 2025. 43:723–49

The *Annual Review of Immunology* is online at
immunol.annualreviews.org

https://doi.org/10.1146/annurev-immunol-082323-035455

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## Keywords

Epstein-Barr virus, inborn errors of immunity, CD8+ T cells, infectious mononucleosis, lymphoproliferation

## Abstract

Inborn errors of immunity (IEIs) represent unique in natura models that uncover key components of immunity in humans, in particular those that predispose to infections. Epstein-Barr virus (EBV) is one of the most common opportunistic infectious agents in humans and is responsible for several diseases, including infectious mononucleosis, nonmalignant and malignant lymphoproliferative disorders, hemophagocytic lymphohistiocytosis, and smooth muscle and epithelial tumors. For most individuals, EBV infection persists for life without pathological consequences. IEIs that do not predispose to EBV infection suggest that innate and humoral responses are not necessary or redundant for the immune response to EBV. IEIs associated with high susceptibility to EBV infection provide unequivocal genetic proof of the central role of CD8+ T cell responses in immunity to EBV. They also highlight the distinct steps and pathways required for, on the one hand, the effector cytotoxic functions of CD8+ T cells and, on the other hand, the expansion and maturation of cytotoxic CD8+ T cells.

<footnote n="1">¹Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Paris, France; email: sylvain.latour@inserm.fr</footnote>

<footnote n="2">²Institut Imagine, Université Paris Cité, Paris, France</footnote>
# 1. INTRODUCTION

In 1964, Epstein and Barr discovered a new virus in Burkitt lymphoma cells isolated from a Ugandan patient (1). Soon thereafter, the Epstein-Barr virus (EBV) was shown to be the first virus known to cause cancer, mostly lymphoma and carcinoma (2). More than 60 years later, EBV infection is recognized as one of the most common opportunistic infections in humans (3). EBV persists latently throughout life, remaining silent most of the time. Nearly all adults worldwide (>90%) are healthy carriers of EBV. The primary infection occurs mainly during childhood and is usually asymptomatic. However, in adolescents and adults EBV infection can trigger infectious mononucleosis (IM), a self-limiting, often benign lymphoproliferative disease, reflecting a strong immune response (4, 5). EBV is orally transmitted by infectious viral particles contained in the saliva that exhibit a preferential tropism for B lymphocytes and epithelial cells in the oropharynx (6, 7).

# 2. EPSTEIN-BARR VIRUS LIFE CYCLE AND INFECTION

EBV belongs to the human herpesvirus family, which consists of large, stable, double-stranded DNA genomes enabling the establishment of both replicative/productive lytic and latent infections in host cells (6–8). The EBV genome persists in cells as an episome that codes for more than 80 proteins and 40 functional untranslated RNAs. It is thought that EBV recently evolved to acquire unique features depending on a set of latent viral genes encoding latent membrane signaling proteins 1 and 2 (LMP-1 and -2), nuclear regulatory proteins (EBNA1, -2, -3A, -3B, -3C, and LP), and functional RNAs. In B lymphocytes, expression of these viral products results in strong and potentially unlimited proliferation and can transform proliferating cells into cancer. LMP-1 and LMP-2A, the two major viral proteins involved in the immortalization of B cells, mimic constitutive activation of the B cell receptor and the B cell costimulatory molecule CD40, hijacking host signaling machinery.

The general scheme is that EBV exploits B lymphocyte biology to persist and replicate in the host (6–8). During the primary infection, EBV crosses the overlying epithelial barrier of Waldeyer's tonsillar ring in the oropharynx to infect naive B cells. Some epithelial cells permisive to EBV entry are also infected; EBV actively replicates in these cells, thereby amplifying the infection of naive B cells through the production and shedding of viral particles. Entry of EBV into B and epithelial cells depends on viral envelope glycoproteins that interact with the complement receptor CD21 and MHC-II molecules on B cells, as well as on nonmuscle myosin IIA, neuropilin, and Ephrin receptor A2 molecules on epithelial cells (9, 10). This lytic productive infection (i.e., the lytic cycle) depends on the expression of EBV lytic genes coding for structural and regulatory proteins necessary for the replication and encapsidation of the viral DNA. Afterward, EBV lytic genes are downregulated, and a latent infection through full expression of EBV latent genes (referred to as the EBV latency III program) is initiated, triggering uncontrolled expansion of infected B cell lymphoblasts in tonsils and other pharyngeal tissues. In that respect, in vitro EBV infection of B cells from peripheral blood mononuclear cells results in lymphoblastoid cell lines (LCLs) expressing the EBV latency III program, which causes perpetual growth. In IM, EBV-infected B cells rapidly expand and are detected in the blood, where they represent up to 10% of circulating B cells. Most of these highly proliferating B cells are eliminated by the immune response, and the few that escape progressively shut down EBV gene expression, becoming invisible to the immune system. Afterward, they repopulate lymphoid organs, including tonsils, where they differentiate into long-lived memory B cells. These cells represent fewer than 0.001% of memory B cell pools and constitute the EBV reservoir, in which EBV episomes (with around 10 copies per cell) persist for life. Only EBERs (Epstein-Barr virus-encoded small RNAs) of EBV
are detectable at this stage (referred to as the EBV latency 0 program). The productive EBV lytic cycle can be reactivated in these reservoir cells when they differentiate into plasma cells, likely in response to antigen recognition. These plasma cells, in turn, produce and release viral particles, initiating new infections of epithelial cells and B lymphocytes. Therefore, reactivation of EBV occurs regularly throughout life and is controlled by the immune system. Rarely, EBV infects and persists in T lymphocytes, natural killer (NK) cells, and smooth muscle cells.

### 3. EPSTEIN-BARR VIRUS-ASSOCIATED PATHOLOGIES

The periodic reactivation of lytic and latent EBV programs throughout life is thought to be a cause of cancer even in subjects considered to be immunocompetent. An estimated 200,000 cancer cases per year worldwide are attributable to EBV, representing up to 1% of the global burden of cancers (2). EBV infection also induces hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory disorder characterized by dysregulated activation and expansion of CD8+ T cells that produce large amounts of IFN-γ, initiating secondary activation of monocytes and macrophages. In this setting, highly activated and phagocytic macrophages infiltrate lymph nodes, bone marrow, spleen, and liver, causing a cytokine storm, tissue damage, and organ failure (11, 12).

EBV latent programs in infected cells drive both nonmalignant diseases and their malignant counterparts (2, 13, 14). The most frequent malignant forms are of B cell and epithelial origin; epithelial cancers preferentially occur in adults. Nonmalignant diseases comprise the B cell lymphoproliferative diseases (B-LPDs), including posttransplant B cell proliferation and hairy leukoplakia, an epithelial/mucosal proliferative disease. The corresponding forms of cancer include Hodgkin lymphoma, diffuse large B cell lymphoma, and Burkitt's lymphoma for B cells, as well as nasopharyngeal carcinoma and gastric carcinoma for epithelial cells.

Infections of NK, CD4, CD8, and/or γδ T cells, termed chronic active EBV infections (CAEBVs), are characterized by high loads of EBV associated with the presence of blood-circulating EBV-infected T and/or NK cells that can persist for years (2, 15). Nonmalignant forms of CAEBV include systemic and cutaneous T/NK cell lymphoproliferations that progressively or suddenly evolve into aggressive and malignant T/NK cell lymphoproliferative diseases (T/NK-LPDs), which are frequently associated with severe HLH. In CAEBVs, EBV-infected T/NK cells represent the main reservoir of EBV since high EBV loads are not relieved by B cell depletion. Initially, CAEBVs were described only in Asian and Latin American populations; however, recent observations indicate that individuals of Caucasian and African origin are also prone to developing CAEBVs, suggesting that CAEBVs are underdiagnosed in Western countries (16). EBV infection of smooth muscle cells is associated with smooth muscle tumors (EBV+ SMTs; also known as leiomyomas), with a clinical course ranging from indolent to aggressive (17). The mechanisms of EBV entry and persistence into T, NK, and smooth muscle cells are unclear but are thought to differ from those of B and epithelial cells (14). Finally, EBV infection and persistence represent a risk factor for the development of autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (18–20).

### 4. IMMUNE RESPONSES IN COMPETENT HOSTS

Most of our knowledge about the competent immune responses at work in EBV infection comes from studies of individuals who developed IM in the course of the primary infection (21). IM is thought to represent an exacerbated form of the normal immune response that occurs in asymptomatic individuals. IM is characterized by rapid expansion of activated cytotoxic CD8+ T cells that first recognize antigenic peptides derived from EBV lytic proteins and then recognize peptides derived from EBV latent proteins. The importance of these responses is exemplified
by the accumulation of EBV-specific CD8⁺ T cells in blood, which can represent up to 40% of circulating T cells at the peak of IM (21–23). To a lesser extent, CD4⁺ T cells are also activated; these include cytotoxic CD4⁺ T cells, which have a more diverse repertoire of EBV antigens than do CD8⁺ T cells. In this context, incomplete HLH can sometimes be initiated by overactivated CD8⁺ T cells, reflecting the severity of IM. Primary EBV infection also activates innate responses involving the expansion of early-differentiated KIRnegCD16negCD56dim NK cells and Vγ9Vδ2 T cells (24). These responses are particularly active in infants in the early phase of the infection, before the establishment of a CD8⁺ T cell response, and are thought to prevent the dissemination and amplification of infection by rapidly eliminating lytically and latently EBV-replicating cells (21), which may explain the absence of IM symptoms in infants.

Different antibodies, including antibodies against the viral capsid and latent EBV protein (anti-EBNA), are produced during EBV infection and represent useful markers of the infection (4). These antibodies seem not to play an important role in immunity to EBV. They have little or no effect on proliferating EBV-transformed B cells, which may explain why they are likely dispensable.

EBV appears to be unique among viruses in its capacity to induce strong proliferation of primary infected B cells. Thus, the immune system faces a remarkable challenge with EBV infection. Notably, it needs to rapidly increase the numbers of antigenic cytotoxic CD8⁺ T cells to counteract and eliminate quickly dividing infected B cells (21, 23, 25). In such a context, the proliferative potential of CD8⁺ T cells can be extraordinarily high, with the cell number doubling every 4 to 6 h (26). Once the primary infection is controlled, the EBV-specific T cell pool contracts and differentiates into memory T cells (22). The remaining EBV-specific memory T cells may account for up to 2.5% of circulating memory T cells and more than 20% of T cells in the tonsils. When EBV is reactivated in reservoir B cells, an anamnestic response is rapidly activated to avoid further viral dissemination and/or B cell expansion. The persistence of EBV throughout life may affect the overall pattern of immune responses, as has been demonstrated with cytomegalovirus (CMV) infection (26–28), and may have provided a selective advantage during evolution. However, in the case of EBV such modifications or effects are difficult to bring to light, as more than 90% of humans are asymptomatic carriers of EBV.

## 5. EPSTEIN-BARR VIRUS INFECTION IN ACQUIRED IMMUNODEFICIENCIES

Life-threatening EBV infections, consisting of polyclonal expansions of highly proliferating EBV-infected B cells, are a common complication in patients with acquired immunodeficiencies, such as organ transplant recipients receiving immunosuppressive therapeutics, HIV-infected patients with acquired immunodeficiency syndrome (AIDS), and patients with inflammatory bowel disease under immunomodulatory treatments (29). Such patients can also develop EBV⁺ lymphoma and EBV⁺ SMTs. This information supports the concept that EBV reactivations are frequent throughout the lifetime and are tightly controlled by the immune system.

## 6. PRIMARY IMMUNODEFICIENCIES AS UNIQUE MODELS TO DECRYPT COMPONENTS OF EPSTEIN-BARR IMMUNITY

More than 500 inborn errors of immunity (IEIs), also known as primary immunodeficiencies, have been identified to date (30). Notably, the characterization and the study of IEIs predisposing to severe EBV infection provide important knowledge on components or pathways necessary for an efficient immune response to EBV. Conversely, IEIs not associated with a particular susceptibility to EBV are informative about components that are not necessary for immunity to EBV. First,
innate immune responses either are not particularly critical or are redundant for the immune con-
trol of EBV, for example, type I interferon-dependent pathways that are crucial for immunity to
other viral infections and NK cell deficiencies (30, 31). Second, IEIs associated with B cell defi-
ciencies and hypo- or dysgammaglobulinemia provide information about the role of the humoral
response and factors required for EBV entry and life cycle. Susceptibility to EBV infection is not
a characteristic of IEIs with selective B cell immunodeficiencies (CD40, CD19, CD81, etc.), in
which B cells are present and permissive to transformation by EBV, at least in vitro (31). How-
ever, it might be that in IEIs causing a severe block in B cell development with no mature B cells,
patients are resistant to EBV infection because EBV cannot establish a primary infection in the
absence of B cells. For example, male patients with X-linked agammaglobulinemia (XLA) caused
by mutations in *BTK* are characterized by the absence of B cells and show no detectable EBV in
the throat or in the blood (32). Moreover, EBV-specific cytotoxic T cells are not detectable in XLA
patients, consistent with resistance to EBV infection. These observations highlight that B cells are
strictly necessary for both the primary and the latent infection and suggest that, in the absence
of B cells, epithelial cells or other cell types permissive to EBV (T, NK, and smooth muscle cells)
could not be infected. Therefore, antibodies produced in response to EBV are not sufficient to
confer protective immunity to EBV (4, 21). Along these lines, normal anti-EBV serology has been
observed in most patients with IEIs predisposing to severe EBV infections.

The identification and characterization of IEIs causing high susceptibility to severe EBV infec-
tions provide unequivocal genetic proof of the central role of CD8+ T cell responses in immunity
to EBV. This is not a surprise, considering the high magnitude of CD8+ T cell responses in im-
munocompetent individuals. In contrast, other T cell subsets appear to be either unnecessary or
redundant for immunity to EBV. Specifically, defects in CD4+ T cells (in human leukocyte anti-
gen class II deficiencies), T helper 1 (Th1) cells (in deficiencies of the IL-12/IFN-γ axis, including
T-bet/TBX21 deficiency) (33), Th17 cells (in STAT3 deficiency), T follicular helper cells (in ICOS
deficiency), and mucosal-associated invariant T and invariant natural killer T (iNKT) cells (in
RORC deficiency) (34) are not associated with susceptibility to severe EBV infection. However,
CD4+ T cells, NK cells, and iNKT cells are reduced in several IEIs predisposing to EBV in-
fection. Thus, these alterations could participate in the immunodeficiency setting responsible for
EBV susceptibility.

IEIs associated with severe impaired T cell development (e.g., *IL2RG*, *JAK3*, *IL7RA*, *CD3*
subunits, *RAG1/2*, *ZAP70*) are also not characterized by susceptibility to severe EBV infections,
in contrast to what would be expected (31). This finding is probably explained by severe in-
fections very early in life that develop in these immunodeficiency backgrounds, which often
require patients to undergo bone marrow transplantation before they encounter EBV. More-
over, the existence of B cell defects associated with some of these T cell deficiencies may
not allow the establishment of EBV infection. However, severe EBV infections manifesting
mostly as B-LPDs or HLH are occasionally to frequently observed in several IEIs in which
T cell development is not (or only moderately) altered but T cell responses are impeded (31).
These IEIs—such as deficiencies in *GATA2*, *DADA2* (35–37), *STIM1*, *SLP-76* (38), *DEF6* (39),
*DIAPH1* (40), *NFKB1*, *MST1/STK4*, *WAS/WASP*, *DOCK8*, and *CORO1A*, as well as gain-of-
function mutations in *PIK3CD* and *PIK3R1*—are associated with variable alterations in T cell
survival, proliferation, migration, synapse formation, and/or effector functions and can also affect
other immune cells (31).

IEIs associated with high susceptibility to severe EBV infection represent a subgroup of IEIs
in which the prevalence of severe EBV infections is high, with 30% to 90% of patients having
developed at least one episode of severe EBV infection in childhood or adolescence (30, 41,
42) (Table 1). Although EBV-related pathologies are the most severe infectious consequence,
<table><caption>Table 1 Gene defects and associated EBV clinical manifestations</caption><thead><tr><th rowspan="2">Gene</th><th rowspan="2">Severe EBV infection</th><th colspan="6">EBV manifestations</th><th rowspan="2">Other infections</th><th rowspan="2">Other symptoms</th></tr><tr><th>HLH</th><th>SIM/chronic infection</th><th>Nonmalignant B-LPD</th><th>Malignant B-LPD</th><th>T/NK-LPD (CAEBV)</th><th>SMT</th></tr></thead><tbody><tr><td>SH2DLA (≥100)</td><td>++++</td><td>+++</td><td>-</td><td>-</td><td>++</td><td>-</td><td>-</td><td>-</td><td>EBV<sup>neg</sup> B lymphoma (≥20)</td></tr><tr><td>XLAP (≥100)</td><td>++</td><td>++</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>++</td><td>IBD (≥30), inflammation (≥20)</td></tr><tr><td>IL27RA (3)</td><td>++++</td><td>-</td><td>++++</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td><td>None</td></tr><tr><td>CTPSI (19)</td><td>++++</td><td>-</td><td>+++</td><td>++</td><td>+</td><td>-</td><td>-</td><td>++++</td><td>None</td></tr><tr><td>R4SGRP1 (9)</td><td>++++</td><td>-</td><td>+++</td><td>+++</td><td>++</td><td>-</td><td>+ (2)</td><td>++++</td><td>Autoimmunity, inflammation/allergy (5)</td></tr><tr><td>ITK (25)</td><td>++++</td><td>+ (2)</td><td>+++</td><td>++++</td><td>++</td><td>-</td><td>+ (1)</td><td>++</td><td>Autoimmunity</td></tr><tr><td>MAGTI (≥50)</td><td>+++</td><td>+ (1)</td><td>++</td><td>++</td><td>++</td><td>-</td><td>-</td><td>+++</td><td>Autoimmunity, multisystemic abnormalities</td></tr><tr><td>CD27 (30 + 3 asympt.)</td><td>++++</td><td>+ (6)</td><td>+++</td><td>+++</td><td>++</td><td>-</td><td>-</td><td>+</td><td>EBV<sup>neg</sup> B lymphoma? (1)</td></tr><tr><td>CD70 (15 + 1 asympt.)</td><td>++++</td><td>-</td><td>++</td><td>++</td><td>+++</td><td>-</td><td>-</td><td>++</td><td>Inflammation/allergy, autoimmunity</td></tr><tr><td>TNFRSF9 (9 + 3 asympt.)</td><td>+++</td><td>-</td><td>+++</td><td>++</td><td>++</td><td>+ (3)</td><td>-</td><td>+</td><td>Chronic diarrhea, fever, autoimmunity</td></tr><tr><td>TNFSF9 (1)</td><td>++++</td><td>-</td><td>+++</td><td>-</td><td>-</td><td>-</td><td>+</td><td>-</td><td>EBV<sup>+</sup> T lymphoma? (3)</td></tr><tr><td>C4RMIL2 (≥80)</td><td>+</td><td>-</td><td>+</td><td>-</td><td>-</td><td>-</td><td>+ (15)</td><td>++++</td><td>Inflammation/allergy</td></tr><tr><td>CD16 (1 + 2 asympt.)</td><td>++++</td><td>-</td><td>+++</td><td>-</td><td>-</td><td>+ (1)</td><td>-</td><td>-</td><td>None</td></tr></tbody></table>

Numbers in parentheses correspond to numbers of patients.

Dash indicates 0% or no known cases; + indicates 0-25%; ++ indicates 25-50%; +++ indicates 50-75%; +++++ indicates 75-100%.

Abbreviations: asympt., asymptomatic individuals; B-LPD, B cell lymphoproliferative disease; CAEBV, chronic active EBV infection; C4RMIL2, capping protein regulator and myosin 1 linker 2; CTPSI, CTP synthetase 1; EBV, Epstein-Barr virus; HLH, hemophagocytic lymphohistiocytosis; IBD, inflammatory bowel disease; IL27RA, α chain of the IL-27 receptor; ITK, IL-2-inducible tyrosine kinase; MAGTI, magnesium transporter 1; R4SGRP1, RMS guanyl-releasing protein 1; SIM, severe infectious mononucleosis; SMT, smooth muscle tumor; T/NK-LPD, T/natural killer cell lymphoproliferative disease; TNFRSF9, tumor necrosis factor superfamily member 9; TNFSF9, tumor necrosis factor superfamily member 9; XLIP, X-linked inhibitor of apoptosis.
patients often experience infections by other pathogens to a variable degree, depending on the
affected immune pathways/components. Immune dysregulation disorders, such as autoimmune
and inflammatory diseases, can also occasionally or frequently develop in these patients.

Furthermore, these IEIs can be classified according to the type of EBV-driven diseases they confer and the immune defects they cause (Figure 1). Such a classification highlights at least two critical distinct steps in the CD8+ T cell response: antigen-induced CD8+ T cell expansion and the effector cytotoxic CD8+ T cell response. Defects in these two steps underlie distinct physiopathological mechanisms. For example, EBV-driven HLH appears to be caused by gene alterations affecting the cytotoxic activity of NK and CD8+ T cells and can be viewed as a T cell lymphoproliferative syndrome because, in this context, the activation and expansion of EBV-specific T cells, stimulated by the persistence of EBV-infected B cells, are pronounced and sustained. In contrast, gene defects impeding the expansion of EBV-specific T cells result in the accumulation of EBV-infected B cells evolving into B-LPDs; the resulting diseases can be considered B cell lymphoproliferative syndromes. However, HLH symptoms can sometimes develop secondary to or in the course of B-LPDs.

7. INBORN ERRORS OF IMMUNITY WITH HIGH RISK FOR EPSTEIN-BARR VIRUS INFECTION CAUSED BY DEFECTS IN THE LYMPHOCYTE CYTOTOXICITY EFFECTOR RESPONSE

Gene alterations that cause defects in the cytotoxic activity of NK and CD8+ T cells preferentially underlie EBV-induced HLH. They include mutations in *RAB27A*, *UNC13D*, *STX11*, and *LYST*, which impair the exocytosis pathway of cytolytic granules in NK and CD8+ T cells, and mutations in *PERF1*, which encodes perforin, a key mediator of cytotoxicity contained in granules. In this group of diseases, termed familial HLH, HLH often occurs in response to an infectious trigger, which is frequently EBV (30% to 60% of cases) (11, 12).

7.1. SH2D1A/SAP Deficiency

Initially discovered in 1970s, the X-linked lymphoproliferative syndrome type 1 (XLP-1; also known as Purtilo syndrome) was the first viral predisposition reported to have a Mendelian segregation and also the first to be genetically resolved (41, 43, 44). XLP-1 predisposes patients to developing severe HLH upon exposure to EBV. More than 100 patients with XLP-1 have been reported. Remarkably, they are uniquely prone to EBV infection and do not develop infections caused by other pathogens. XLP-1 is characterized by a triad of symptoms including fulminant infectious mononucleosis (FIM) at first EBV exposure (75%); B lymphoma (30%), with half of cases unrelated to EBV infection; and hypogammaglobulinemia (30%). FIM corresponds to unchecked IM characterized by a massive expansion of activated CD8+ T cells associated with full-blown HLH that is often lethal (in >90% of cases in early studies), in contrast to the self-limiting IM observed in immunocompetent individuals. In this context, high levels of EBV-infected B cells in blood have been observed and could represent up to 30% of peripheral blood mononuclear cells (16). This observation indicates that, despite rapid activation of CD8+ T cells, the elimination of infected cells is impaired. Correspondingly, NK cells and CD8+ T cells in patients with XLP-1 have impaired cytotoxic activity and can neither control the in vitro transformation by EBV of B cells into LCLs nor kill established LCLs.

Genetic studies of XLP-1 have revealed the crucial and selective function of immune trans-
membrane receptors of the SLAM family (SLAMF-Rs) in the activation of CD8+ T and NK
cell cytotoxicity responses toward EBV-infected B cells. XLP-1 is caused by genetic lesions in
an X-linked gene, SH2D1A, that codes for SAP (SLAM-associated protein), a small intracellular
<figure><img src="image_6.png" /><figcaption>Figure 1</figcaption></figure>

Normal and pathological immune responses to EBV. In healthy individuals, EBV infection triggers rapid expansion of EBV-specific T cells to counteract and eliminate EBV-infected proliferating B cells. IEIs that cause impaired T cell expansion (*CTPS1*, *RASGRP1*, *ITK*, *CD27*, *CD70*, *TNFRSF9*, *TNFSF9*, and *CARMIL2* deficiencies) are associated with the persistence of EBV-infected (EBV⁺) cells, which include B cells mostly and, more rarely, T, NK, or smooth muscle cells; this persistence causes malignant or nonmalignant B-LPD, T/NK-LPD, or EBV⁺ SMT. *IL27RA* deficiency or anti-IL-27 AA causes SIM without B-LPD. IEIs that impair T cell cytotoxicity or killing of EBV-infected cells (e.g., *UNC13D*, *STX11*, *STXBP2*, *RAB27A*, *LYST*, and *SH2D1A* deficiencies) result in the persistence of EBV-infected B cells, leading to hyperactivation of T cells that cannot kill EBV-infected B cells but rather continue to expand and produce large amounts of proinflammatory cytokines, including IFN-γ. In this setting, macrophages are activated by IFN-γ and become phagocytic, leading to HLH. EBV-driven HLH in *XIAP* deficiency is not clearly understood. The myeloid cell compartment in association with abnormal inflammasome activation is strongly suspected to play a major role. The role of EBV in triggering HLH might be explained by excessive apoptosis of activated EBV-specific *XIAP*-deficient T cells, which could promote macrophage activation and HLH through unrestricted activation of inflammasomes and TNF-induced inflammatory forms of cell death (both of which depend on *XIAP* for their regulation). Abbreviations: AA, autoantibodies; B-LPD, B cell lymphoproliferative disease; EBV, Epstein-Barr virus; HLH, hemophagocytic lymphohistiocytosis; IEI, inborn error of immunity; SIM, severe infectious mononucleosis; SMT, smooth muscle tumor; T/NK-LPD, T/natural killer cell lymphoproliferative disease. Figure adapted from Reference 31.
signaling adapter molecule composed of a single SH2 (Src homology domain 2) (45-47) that is preferentially expressed in T and NK cells. Through SH2, SAP selectively binds to immunoreceptor tyrosine-based switch motifs containing intracytoplasmic SLAMF-R domains (48, 49), thereby coupling SLAMF-Rs to intracellular signaling cascades. Mechanistically speaking, the interaction of SAP with SLAMF-Rs has two consequences. The first is to block the recruitment of tyrosine phosphatases, such as SHP-1 and SHP-2, which are signaling inhibitory/regulatory molecules, and the second is to recruit the protein tyrosine kinase FYN. Both mechanisms enable the propagation of active signals involving various signaling molecules (e.g., Vav-1, PLCγ-1, LAT, Dok2, SHIP) (50, 51). Thus, the behavior of SLAMF-Rs can be modulated, depending on the intracellular levels of SAP, SHP-1, and SHP-2.

In the absence of SAP, as in patients with XLP-1, the stimulatory functions of SLAMF-Rs are switched off and SLAMF-Rs can exert only inhibitory functions (through the recruitment of SHP-1/2). SLAMF-Rs are broadly expressed on hematopoietic cells and mediate cell-cell interactions via homotypic self-ligand recognition; the exception is 2B4, a SLAMF-R expressed on T and NK cells that recognizes CD48, which was initially identified as a B cell surface antigen induced upon EBV infection (52). EBV-transformed B cell lines express high levels of SLAMF-Rs, including NTB-A and CD48 (53). At least two SLAMF-Rs expressed on NK and CD8+ T cells, NTB-A (SLAMF6) and 2B4, are involved in the killing of LCLs through their ability to activate and enhance cytotoxic responses (54-58). In the absence of SAP, the capacity of NTB-A and 2B4 to promote cell cytotoxicity is converted into an inhibitory function, causing a broad suppression of cytotoxic responses. This suppression results from a transinhibition of activating receptors of cytotoxicity such as CD16 and NCRs (natural cytotoxicity receptors) by 2B4 and NTB-A (54, 59-61). Moreover, conjugate and synapse formation between T/NK cells and EBV-infected B cells decreases in the absence of SAP (50, 62), likely further impairing the cytotoxic responses of SAP-deficient T cells.

Studies of female XLP-1 carriers (63) and several XLP-1 patients with somatic genetic rescue that restored SAP expression in T cells (64, 65) provided evidence that the lower vulnerability to EBV in XLP-1 is more a problem of a global lack of immune reactivity of T cells toward B lymphocytes as antigen-presenting cells, rather than an issue with the virus itself. Furthermore, the selective activation or reactivity defects of SAP-deficient NK/CD8+ T cells toward B cells depend on high levels of SLAMF-Rs expressed on B cells (which increase further upon EBV infection). In contrast, other cells, such as dendritic cells and nonhematopoietic cells, do not express (or express low levels of) SLAMF-Rs. As a consequence, immunity to other pathogens is preserved as long as they do not target B cells (41, 43).

Moreover, other SLAMF-SAP-dependent abnormalities may participate in or amplify the severity of EBV disease in XLP-1 patients (42). These include defects in T cell receptor (TCR) restimulation-induced cell death (RICD) that are involved in shrinking the pool of activated antigen-specific T cells during immune responses (66), abnormal NK cell education leading to increased cytotoxic responses toward nonhematopoietic tissue (67), and a complete absence of iNKT cells (68-70). Notably, iNKT cells can limit the proliferation of EBV-transformed B cells in vitro (71). Interestingly, reduced numbers or a total absence of iNKT cells has been observed in several other IEIs predisposing to EBV infection (42). Like NK cells, iNKT cells might be involved in early phases of the immune response to EBV.

## 7.2. XIAP Deficiency

In 2006, a second form of XLP (XLP-2) was identified in six male patients who developed FIM upon EBV infection (72). They were not carriers of mutations in *SH2D1A* but rather had
hemizygous mutations in a neighboring gene named XIAP, which codes for the X-linked inhibitor of apoptosis (12, 73–75). XIAP is an inhibitor of proximal caspases and also has E3 ubiquitin ligase activity. It is involved in several pathways, including inhibition of RICD in lymphocytes, regulation of tumor necrosis factor (TNF)- or lipopolysaccharide-stimulated necroptosis and inflammatory cell death, restriction of inflammasome activation, and activation of the NOD family of pattern recognition receptors (NOD1 and NOD2) (74, 75). More than 100 patients with XIAP deficiency, including female carriers who are symptomatic due to an abnormal X inactivation pattern, have now been reported (76–78). Although EBV-driven HLH is one of the most severe phenotypes, found in 30% of patients, XLP-2 significantly differs from XLP-1 in other clinical features, including splenomegaly and various inflammatory manifestations (e.g., a Crohn-like inflammatory bowel disease that develops in 30% of patients) (75, 79). Other genetic and/or environmental factors that may influence the clinical phenotype include genetic polymorphisms in CD40LG (80). Physiopathological mechanisms underlying EBV susceptibility are also clearly different from those of SAP deficiency. Unlike in patients with XLP-1, the cytotoxic responses of NK and CD8+ T cells, including NTB-A- and 2B4-dependent responses, are normal in patients with XLP-2 (72, 81). However, activated XIAP-deficient T cells show increased apoptosis/RICD and reduced expansion (72). The myeloid cell compartment in association with abnormal inflammasome activation, which may be due to excessive necroptosis and apoptosis, is strongly suspected to play a major role in EBV-driven HLH (75, 82, 83).

## 8. INBORN ERRORS OF IMMUNITY WITH HIGH RISK FOR EPSTEIN-BARR VIRUS INFECTION CAUSED BY DEFECTS IN THE EXPANSION AND DIFFERENTIATION OF EPSTEIN-BARR VIRUS-SPECIFIC T CELLS

A key step in the immune response to EBV is the rapid expansion of the EBV-specific CD8+ cytotoxic T cells necessary to compete with and eliminate quickly dividing infected B cells. Current models of expansion and terminal differentiation of antigen-specific T cells into effector cells indicate that expansion depends on at least three distinct signals, namely those provided by the TCR (signal 1), costimulatory molecules (signal 2), and cytokines (signal 3). These signals synergize to achieve and maintain the expansion of mature effector CD8+ T cells (84–86). Several IEIs predisposing to EBV infection are caused by genetic lesions affecting components involved in these three pathways, highlighting the nonredundant requirements of these pathways to mount and sustain the expansion of effector EBV-specific T cells during EBV infection. Consistent with a defective expansion of EBV-specific T cells that does not directly impact cell cytotoxicity activity, HLH is a rare or nondominant manifestation associated with these IEIs, which are characterized mainly by B-LPDs. Patients often exhibit decreased levels of EBV-specific T cells in blood, an observation that is consistent with the impaired defective expansion of EBV-specific T cells in vitro.

### 8.1. Defects in Signal 1: Deficiencies in Downstream Components of the T Cell Receptor

Virtually all gene lesions affecting components of the TCR signaling machinery and downstream pathways can cause impaired control of EBV infection, as discussed above (31). However, only a few IEIs affect downstream TCR signaling components that are associated with a high incidence of severe EBV-driven diseases. These IEIs, including CTP synthetase 1 (CTPS1), RAS guanyl-releasing protein 1 (RASGRP1), and IL-2-inducible tyrosine kinase (ITK) deficiencies, are characterized mainly by impaired proliferation of T cells in response to TCR engagement but are not restricted to EBV-specific T cells.
**8.1.1. CTPS1 deficiency.** CTPS1 is an enzyme responsible for de novo synthesis of the nucleotide CTP, a key component of nucleic acid metabolism. The concentration of CTP is limiting in cells and depends on a salvage pathway (from nucleic acid degradation) and a de novo pathway. CTP is required for DNA replication and consequently proliferation (87). CTPS1 is broadly expressed across tissues (88). Studies of Ctpsl-deficient mice have shown that CTPS1 is essential for life and is required for the maintenance and growth of tissues and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells (88).

CTPS1 deficiency has been identified in 18 patients who experienced severe early-onset EBV infections (89–91). All of these patients carried the same homozygous mutation in the *CTPS1* gene. This mutation reduces CTPS1 expression by 80%, with no effect on enzymatic activity, which translates into 20% residual enzymatic activity in the patients’ cells. This residual activity likely explains why the patients had no developmental abnormalities, in contrast to mice lacking *Ctpsl* (88). The proliferative capacity of CTPS1-deficient T cells in response to TCR stimulation is severely and selectively compromised. Downstream T cell activation signals and effector functions, such as cytotoxicity and cytokine production, are preserved. Activated CTPS1-deficient T cells start to divide and are soon arrested in the G₁ phase of the cell cycle, consistent with the role of CTPS1 in DNA synthesis. Importantly, CTPS1 expression in activated T cells depends strongly on TCR signaling. CTPS1 expression is low in resting T cells and rapidly upregulated upon TCR engagement, but not in response to IL-2 or IL-15. Similar findings have been reported in mice in which *Ctpsl* is inactivated in T cells (88). Interestingly, proliferation of LCLs also depends on CTPS1 and might explain the low occurrence of B cell lymphoma, whereas all patients developed severe EBV infection. Thus, CTPS1 deficiency represents a clear example in which expansion of T cells is selectively impeded, highlighting the critical role of T cell expansion in the immune response to EBV.

**8.1.2. RASGRP1 deficiency.** Nine patients with a deficiency in the RASGRP1 protein, due to biallelic loss-of-function mutations in *RASGRP1*, have been reported (92–97). RASGRP1 is a diacylglycerol-regulated guanidine exchange factor for the small GTPase Ras, expressed mainly in T and NK cells (98). The principal known role of RASGRP1 is to activate the Ras-MAPK/ERK pathway downstream of the TCR and activating NK receptors. As expected, RASGRP1-deficient T cells exhibit markedly decreased Ras-MAPK/ERK pathway activation. RASGRP1-deficient T cells show defects in proliferation, migration, and cytotoxic activity, consistent with the central role of the MAPK pathway in many cellular responses. Some patients also exhibit signs of abnormal TCR repertoires, which may account for the autoimmune manifestations found in half of patients.

Interestingly, impaired proliferation of RASGRP1-deficient T cells correlates with an inability to upregulate CTPS1 expression in response to TCR stimulation (93). This finding could be explained by the presence of a binding site in the *CTPS1* promoter for the transcription repressor EA2, the regulation of which depends on the MAPK pathway (99). Furthermore, CD27-dependent proliferation, an important pathway involved in expansion of EBV-specific T cells (see Section 8.2.1), is ineffective (93). Thus, predisposition to EBV-driven lymphoproliferation and malignancy associated with RASGRP1 deficiency likely results from defects in the expansion and function of EBV-specific T cells.

**8.1.3. ITK deficiency.** ITK is a protein tyrosine kinase in the BTK/TEC kinase family that is expressed exclusively in T and NK cells. ITK functions in proximal TCR signaling by increasing activation of the PLC-γ1 pathway (through tyrosine phosphorylation) and subsequently dependent downstream pathways, including calcium mobilization and MAPK/ERK (100). Studies in
mice underscore the involvement of ITK in T cell development and in many CD4⁺ and CD8⁺ T cell responses, consistent with its role in proximal TCR signaling. Notably, CD8⁺ T cells fail to expand and differentiate into cytotoxic effector cells (101).

Of 26 patients with ITK deficiency, most (>80%) developed severe EBV infections with frequent lung involvement (41, 102–118). One patient had an EBV⁺ SMT (105). Interestingly, three patients had no EBV-related diseases but developed severe tuberculosis (116). CD4⁺ T cell lymphopenia and hypogammaglobulinemia also appear to be features of ITK deficiency. ITK-deficient T cells from patients show defects in PLC-γ1 activation, Ca²⁺ fluxes, proliferation, and IFN-γ in response to TCR stimulation, consistent with the known role of ITK (102, 116). Thus, in the absence of ITK, TCR signals are altered and/or weakened, likely resulting in deficient expansion and maturation of T cells associated with impaired IFN-γ production.

**8.1.4. MAGT1 deficiency.** Magnesium transporter 1 (MAGT1) is a ubiquitously expressed Mg²⁺ transporter that interacts with the N-oligosaccharyl transferase complex. As such, MAGT1 is involved in the N-glycosylation of proteins, and MAGT1 deficiency is therefore classified as a congenital disorder of glycosylation (119). To date, more than 60 patients with MAGT1 deficiency have been reported (41, 120–126). A few patients with intellectual and developmental delay, with and without signs of immunodeficiency, have also been identified (119), along with patients with platelet dysfunction causing life-threatening bleeding (127, 128). MAGT1 was initially proposed to be directly involved in proximal TCR signaling, which would explain the patients’ immunodeficiency (120, 129). However, several more recent lines of evidence suggest that immunodeficiency and other clinical features result from abnormal protein N-glycosylation of surface molecules, which impairs their function (128, 130). Along these lines, MAGT1 is critical for the glycosylation, expression, and function of NKG2D, a heavily glycosylated activating receptor of cell cytotoxicity that is expressed on CD8⁺ T and NK cells (131, 132). NKG2D promotes the expansion and survival of CD8⁺ T cells during viral infection and activates cell cytotoxicity when engaged through the recognition of stress-induced MHC-I homolog molecules present on the surface of cancer cells and virally infected cells (including by EBV) (133). MAGT1-deficient T cells exhibit a marked loss of NKG2D expression in CD8⁺ T and NK cells that compromises their ability to kill EBV-infected B cells in vitro. MAGT1 deficiency also alters the glycosylation of other important immune receptors involved in the expansion of EBV-specific T cells, such as CD70 (see Section 8.2.1) (130, 134). However, MAGT1 deficiency reveals an important role for NKG2D in immunity to EBV.

**8.2. Defects in Signal 2: Deficiencies in Costimulatory Molecules of the TNF Receptor Family**

Elucidation of the mechanisms underlying the selective susceptibility to EBV in XLP-1 revealed the key role of SLAMF-R-dependent interactions between CD8⁺ T cells and B cells as well as their basic function in activating the killing of EBV-infected B cells. The recent identification of genetic lesions in the costimulatory receptors of TNF receptor (TNF-R) superfamily (TNFRSF) members CD27 and CD137/4-1BB/TNFRSF9 and their ligands CD70 and CD137L similarly explains the susceptibility to EBV associated with these genetic defects. The absence of, or reduced interactions between, TNF-R and TNF ligands expressed on T cells and EBV-infected B cells, respectively, compromises the activation of T cell responses. Such interactions seem to be required especially for the priming, expansion, and differentiation of EBV-specific CD8⁺ T cells into mature cytotoxic effector cells, rather than being directly involved in the activation of cytotoxic responses, as for SLAM-R interactions in XLP-1.
**8.2.1. CD27 and CD70 deficiencies.** Researchers have identified 33 and 16 patients with CD27 or CD70 deficiency, respectively, caused by biallelic mutations in *CD27* or *CD70* (135–142). Although these two IEIs are viewed as phenocopies, they may not be exactly equivalent, as 20% of CD27 patients experience HLH symptoms that are not observed in CD70-deficient patients (141).

CD27 (TNFRSF7) and its ligand CD70 are members of the TNF superfamily and are expressed by most T cell subsets, with the highest expression on resting T cells. In T cells, the role of CD27 is well-characterized. Specifically, it delivers costimulatory signals during TCR activation that enhance T cell survival, proliferation, cytokine production, and cytotoxicity (143, 144). In mice, CD27-CD70 interactions are important for expansion, survival, and effector functions of CD8⁺ T cells during viral infections (145, 146). CD70 expression is weak or undetectable on most hematopoietic cells, with the exception of a small population of B cells, but upregulated on activated dendritic, B, and T cells (137). Notably, high levels of CD70 have been detected on EBV-infected B cells in tonsils of individuals with IM, EBV-transformed B cell lines (LCLs), and B cell lymphoma, consistent with their role as semaphores that signal abnormal B cell behavior (137, 147, 148). Studies of CD70- and CD27-deficient patients have shown that, in the absence of CD70 on EBV-infected B cells or CD27 on T cells, EBV-specific cytotoxic T cells do not expand properly in vitro, and the subsequent killing of EBV-infected cells is decreased (137, 141). In contrast, expansion of CMV-specific T cells appears to be preserved (141). Importantly, EBV-specific T cells can kill EBV-infected B cells irrespective of CD70 expression, further supporting the idea that CD27-CD70 interactions are important for the priming and expansion of CD8⁺ cytotoxic T cells versus being directly involved in the activation of cell cytotoxicity. Furthermore, memory CD8⁺ T cells and EBV-specific CD8⁺ T cells from both CD27- and CD70-deficient patients exhibit low levels of NKG2D, 2B4, perforin, and granzyme B, indicating that differentiation of CD8⁺ T cells into mature effector cells is also altered (139, 141). This impaired CD8⁺ T cell maturation could further compromise the cytotoxic response of CD8⁺ T cells toward EBV-infected B cells. Therefore, the CD27-CD70 pathway appears to be critical for the immune response to EBV, mainly by promoting activation, expansion, and maturation of effector anti-EBV CD8⁺ T cells. Signals delivered by CD27 to T cells when engaged by CD70 (on B cells) likely activate NF-κB or sustain the NF-κB pathway through the recruitment of the TNF-R-associated factor molecules TRAF2 and -5, known activators of NF-κB (149).

**8.2.2. TNFRSF9 and TNFSF9 deficiencies.** Like CD27, TNFRSF9, better known as CD137 or 4-1BB, is a costimulatory molecule characterized by its ability to sustain CD8⁺ T cell responses (150–152). CD137 engagement promotes T cell mitochondrial function and biogenesis, which seems to be one of the mechanisms by which CD137 enhances T cell responses and activates NF-κB (153, 154). Unlike CD27, CD137 is not found on resting T cells, but it is expressed on recently activated antigen-specific T cells (155). The ligand of CD137, CD137L, is expressed by monocytes, dendritic cells, activated B and T cells, smooth muscle cells, and EBV-infected B cells in tonsils of individuals with IM and hematological malignancies including T cell lymphomas and LCLs (156).

Ten patients with CD137 deficiency caused by biallelic mutations in *TNFRSF9* have been reported to have severe EBV-driven B-LPD manifestations similar to those associated with CD27 and CD70 deficiencies (157–160), with the notable exception of three patients who developed cases of CAEBV with overt T/NK-LPDs, one of which was fatal (157, 159, 160). Only one patient with CD137L deficiency has been identified to date (156). This patient had a chronic and fatal EBV infection characterized by high EBV loads, blood-circulating EBV-infected B and T cells, and multiple EBV⁺ SMTs disseminated throughout different organs.
Unlike other IEIs predisposing to EBV, CD27, CD70, and CD137 deficiency have an incom-
plete penetrance. This is particularly obvious for CD137 deficiency, as four individuals (in four
kindreds) with biallelic mutations in *TNFRSF9* were clinically silent, suggesting that additional
genetic and/or environmental factors may be involved. Confirming this hypothesis, an additional
homozygous inactivating pathogenic mutation in *PIK3CD* was discovered in one patient; this mu-
tation was heterozygous in the patient's asymptomatic CD137-deficient sibling. Moreover, the
unique patient with CD137L deficiency was also a carrier of a 22q11.2 deletion causing DiGeorge
syndrome, a developmental syndrome associated with variable immunodeficiency (156). Thus,
the expression and severity of EBV diseases in patients with TNFRSF9 and TNFSF9 deficiency
involved additional genetic factors.

Similar to what is observed in CD27 and CD70 deficiencies, CD137-dependent expansion of T cells and killing activity toward LCLs are abrogated in association with diminished IFN-γ and perforin expression and mitochondrial activity, and CD137L-deficient LCLs fail to induce expansion of EBV-specific T cells. Therefore, the CD137-CD137L pathway appears to be critical for the immune response against EBV-infected B cells as well as for the control of EBV-infected T cells and EBV-infected smooth muscle cells that can express CD137L (156). However, other cell types expressing CD137L, such as dendritic cells and endothelial cells in the microenvironment, might be indirectly involved in these responses. Furthermore, CD137-CD137L interaction also induces expansion of human NK cells (156, 161); therefore, impaired NK cell responses may also contribute to EBV susceptibility (157, 160).

Although they share strong similarities, the CD27–CD70 and CD137–CD137L pathways ap-
pear to be nonredundant to sustain activation, differentiation, and expansion of CD8+ effector
EBV-specific T cells. Their respective contributions may be timely orchestrated, allowing ef-
ficient differentiation of antigen-specific T cells and their prolonged and sustained expansion.
The CD27-CD70 pathway may work first since CD27 is expressed on resting T cells, while the
CD137-CD137L pathway acts later, when CD137 expression is acquired by activated T cells.
Interestingly, there is a mouse model (162, 163) in which transgenic expression of the EBV LMP-
1 and LMP-2A proteins in B cells drives their lymphoproliferation and transformation. In this
model, expression of LMP-1 induces expression of CD70, CD137L, and OX40L (another TNF
ligand) on B cells that promote potent cytotoxic T cell responses (164). This observation further
supports the critical role of CD27 and CD137 pathways in the control of EBV-infected B cells and
highlights the capacity of EBV, via LMP-1 in B cells, to activate the CD27 and CD137 pathways.

8.3. Defects in Signal 3: Defects in the IL-27 Pathway

Although the role of cytokines in the expansion of T lymphocytes is well-established, a selective
role for cytokines in immunity to EBV was only recently identified following the discovery of a
deficiency in the α chain of the IL-27 receptor (IL27RA), revealing the role of the IL-27 cytokine
in the expansion and differentiation of EBV-specific T cells into efficient cytotoxic T cells.

**8.3.1. IL27RA deficiency.** IL27RA deficiency was discovered in three patients with severe IM resulting from biallelic compound heterozygous or homozygous lesions in *IL27RA* (165). Strikingly, all patients developed severe IM; none developed further B-LPDs or other EBV-related clinical manifestations, even 17 years post-IM for one patient. Importantly, one pathogenic *IL27RA* allele is enriched in the Finnish population and predisposes to severe IM, offering further evidence that severe IM is the main clinical phenotype associated with IL27RA deficiency.

IL27RA is expressed in most lymphoid cells (166). IL27RA is low on resting T cells and up-
regulated upon TCR activation. IL-27 is the only cytokine that binds to IL27RA. When bound
to IL-27, IL27RA activates the JAK/STAT pathway, mainly the JAK1/2 and STAT1/3 proteins,
through the gp130 cytokine transducing subunit. IL-27 is a heterodimeric cytokine made of two
molecules, IL-27p28 and EBV-induced gene 3 (EIB3) (167). Antigen-presenting cells, including
dendritic and B cells, are the main source of IL-27. As indicated by its name, EIB3 was initially
identified in EBV-transformed B cell lines and LCLs that are indeed good producers of IL-27
(165, 168, 169).

Early studies showed that IL-27 promotes Th1 differentiation and proliferation of naive CD4+ and CD8+ T cells (166, 170, 171). Furthermore, expansion of virus-specific self-renewing memory-like CD8+ T cells depended on IL-27 in a mouse model of persistent viral infection, likely through expression of IRF1, a transcription factor with the cell-intrinsic ability to sustain cell division (172). Consistent with these observations, IL27RA-deficient T cells from patients fail to properly expand and differentiate into potent anti-EBV effector cytotoxic CD8+ T cells when cocultured with EBV-infected B cell lines (i.e., LCLs) and show impaired cytotoxicity responses. In addition, phosphorylation of STAT1 and STAT3 in response to IL-27 is abrogated in patients' T cells.

As for other IEIs, the selective predisposition to EBV caused by IL27RA deficiency can be
explained by a peculiar link between CD8+ T cells and infected B cells. Indeed, EBV infection
activates the production of IL-27 by naive B cells (165). Thus, this production may be partic-
ularly important in promoting expansion and differentiation of EBV-specific T cells when they
encounter EBV-infected B cells at the beginning of the infection. In support of this hypothesis,
B cell-derived IL-27 is important for the control of persistent lymphocytic choriomeningitis in-
fection in mice (173). However, other cell subsets that produce IL-27, like dendritic and myeloid
cells, may also be involved (174). Furthermore, the role of IL-27 may be particularly important
early in the immune response to EBV, when the antigenic loads or numbers of EBV-infected B
cells are low, since IL-27 exerts a strong synergistic effect on the proliferation of naive T cells
induced by low TCR stimulation.

Other important findings indicate that growth and maintenance of EBV-transformed B cells/
LCLs are dependent on IL-27. This dependency involves an autocrine loop since IL-27-deficient
LCLs obtained by CRISPR-Cas9 technology exhibit low proliferation rates. This finding could
explain why patients with IL27RA deficiency do not develop B-LPD despite having severe IM.

**8.3.2. Anti-IL-27 autoantibodies.** Interestingly, autoantibodies against IL-27 are detected in sera of children and adolescents at the time they experience “classical” acute IM that was considered to be severe, as the patients needed immunosuppressive treatments and/or hospitalization (165). These anti-IL-27 autoantibodies are neutralizing and inhibit IL-27-dependent T cell proliferation in vitro. Thus, these autoantibodies could account for the severity of IM symptoms in these individuals, mimicking IL27RA deficiency. Various neutralizing anticytokine autoantibodies are known to develop in humans and are associated with the occurrence of infectious diseases in individuals harboring these autoantibodies (175). Importantly, these anticytokine autoantibodies can phenocopy genetically determined immunodeficiencies, such as defects in type I and type II interferons, IL-17A/F, or IL-6.

# 9. IMMUNE RESPONSES TO EPSTEIN-BARR VIRUS-INFECTED CELLS OTHER THAN B CELLS

**9.1. Epstein-Barr Virus-Infected Smooth Muscle Cells**

EBV+ SMTs are very rare tumors, often disseminated throughout the body, that result from multiple EBV infections rather than metastasis. EBV+ SMTs develop only in the setting of immunodeficiency (17, 176). They were initially described in patients with AIDS or patients who had received immunosuppressive treatments after organ transplant. Several single cases have been
documented in patients with IEIs; these include severe combined immunodeficiencies, caused by mutations in *ZAP70* or *IL2RG*; GATA2 deficiency; ataxia-telangiectasia; and NEMO deficiency (177, 178). In IEIs predisposing to EBV infection, EBV+ SMTs have been reported in patients with RASGRP1 (two cases), ITK (one case), and CD137L (one case) deficiencies (93, 96, 105, 156). These patients also developed EBV+ B-LPD, with the exception of the patient with CD137L deficiency, in whom the severity of EBV infection manifested exclusively as disseminated EBV+ SMTs despite the presence of significant numbers of circulating EBV-infected T and B cells. This finding might indicate that CD137L (and the CD137L-CD137 pathway) has a specific role in the control of EBV-infected smooth muscle cells.

Intriguingly, the highest incidence of EBV+ SMTs is observed in capping protein regulator and myosin 1 linker 2 (CARMIL2, also known as RLTPR) deficiency (178–182). More than 80 patients with CARMIL2 deficiency have been identified, and 17% of them presented with EBV+ SMTs (178, 181). Strikingly, these patients do not develop other EBV-related manifestations; however, most of them display a persistent, mild EBV viremia, suggesting that there is a defect in their immune control of EBV. In support of these observations, CARMIL2-deficient T cells failed to control the growth of autologous LCLs in vitro. CARMIL2 is a large adaptor scaffolding protein involved in the activation of several pathways, including NF-κB. Notably, CARMIL2 couples the T cell costimulatory molecule CD28 with NF-κB by interacting with the CD28 intracytoplasmic domain (183). However, CD28 deficiency has been reported in three patients who developed only severe human papillomavirus infections, suggesting that the role of CARMIL2 in the immune control of EBV+ SMT cells is independent of CD28 (184). These observations raise the possibility that CARMIL2 is important for other pathways, such as the CD137–CD137L pathway, in light of the CD137L-deficient patient who uniquely presented with EBV+ SMTs. CARMIL2 appears to be a selective and key component for the immune control of EBV+ SMTs, although its exact role remains to be elucidated.

## 9.2. Epstein-Barr Virus-Infected T and Natural Killer Cells

CAEBVs rarely develop in the context of acquired immunodeficiency; however, EBV-infected T cells are frequently detected in HIV-infected children, although these patients do not develop T/NK-LPD (185, 186). The fact that high EBV viremia and circulating EBV-infected T/NK cells can persist for years in patients before they develop an aggressive T/NK-LPD suggests that immune control is not fully competent in these individuals. Along these lines, diminished EBV-specific CD8+ T cells and increased myeloid-derived suppressor cells have been observed in patients with CAEBVs (187, 188). Several isolated cases of CAEBVs have been reported in the context of IEIs; these include patients with a hypomorphic hemizygous *IL2RG* mutation (189), GATA2 haploinsufficiency (190), FANCA deficiency (191), ICF2 syndrome (192), 22q11.2del syndrome (193), IKZF2 deficiency (194), and IKZF3 deficiency (195). These deficiencies are not known to predispose to EBV infection. A common feature of these IEIs is impaired hematopoietic cell development, including early thymic and myeloid differentiation steps. Recent observations suggest that EBV-infected NK and T cells arise from EBV-infected early lymphoid/hematopoietic progenitors, including CD34+ and thymic precursors (196, 197); these findings raise the possibility that, in patients with these IEIs, early lymphoid precursors are more prone to EBV infection, favoring later occurrence of T/NK-LPD.

The identification of four CD137-deficient patients with CAEBVs, three of whom developed T cell lymphoproliferative disease (T-LPD) and one who remained asymptomatic with persistent high EBV viremia and circulating EBV-infected T and NK cells, strongly suggests that the CD137–CD137L pathway is critical for the control of EBV-infected T and NK cells (156, 157,
159). Interestingly, CD16A deficiency was recently discovered in a patient who developed a severe CAEBV. This patient has two CD16-deficient siblings who are clinically silent but show mild EBV viremia (198). CD16A deficiency is caused by allelic genetic lesions in *FCG3RA*. CD16A is a low-affinity receptor for the Fc portion of IgG expressed predominantly on NK and myeloid cells and triggers IgG-dependent cellular responses, such as antibody-dependent NK cell cytotoxicity. Although this observation has been recorded in only one patient so far, it might suggest that antibody responses, thought to be dispensable for the immune control of EBV-infected B cells, could be involved in the control of EBV-infected T and NK cells. In these two examples of deficiency (i.e., CD137 and CD16), additional genetic factors seem to be necessary for disease expression and could modulate its severity. Along these lines, somatic mutations in the JAK/STAT and MAPK/ERK pathways and in the RNA helicase DDX3X occur and accumulate over time in EBV-infected NK and T cells, making CAEBV a premalignant condition (199). In that respect, the TNFRSF9-deficient patient who died of an EBV+ T-LPD had a second germinal genetic lesion consisting of a pathogenic loss-of-function homozygous mutation in *PIK3CD* that increases the proliferation rate of activated T cells (160) and, thus, may represent a germinal driver mutation favoring the accumulation of secondary somatic mutations. PIK3CD deficiency, in conjunction with TNFRSF9 deficiency, likely contributed to the occurrence of a malignant EBV+ T-LPD in the patient. Otherwise, the implied role of additional genetic factors in EBV+ T/NK-LPDs contrasts the mechanisms underlying EBV+ B-LPDs, in which somatic driver alterations seem to play a less important role in the acquisition of malignancy. Therefore, the etiology of CAEBV appears to be complex, resulting from intricate germinal and somatic genetic factors and possibly other environmental factors. However, the TNFRSF9-TNFSF9 pathway seems to be particularly important for restricting EBV-infected T, NK, and smooth muscle cells.

10. CONCLUSION

Over the last 20 years, the discovery and characterization of IEIs causing susceptibility to EBV have significantly advanced our understanding of human immune responses to EBV and EBV-associated diseases. However, several diseases, such as “atypical” EBV infections of T, NK, and smooth muscle cells and EBV-associated autoimmune disorders like multiple sclerosis, remain poorly understood. Although IEIs still represent powerful models for the study of immunity to EBV, resolution of the complex etiology of these diseases will need novel hypotheses and approaches.

DISCLOSURE STATEMENT

The author is not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

S.L. thanks all present and past members of his lab as well as colleagues for their scientific contri-
butions to and collaborations in this field over the years. S.L. also acknowledges the patients and
their families who have made this research possible. S.L. is a senior scientist at CNRS (Centre
national de la recherche scientifique) (France), and his research is supported by INSERM (Insti-
tut national de la santé et de la recherche médicale) (France), La Ligue contre le cancer-équipes
labellisées (France), ANR (Agence nationale de la recherche) (France), SFCE (Société française de
lutte contre les cancers et les leucémies de l'enfant et de l'adolescent), and INCa (Institut national
du cancer) (France).
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