Children with endemic Burkitt lymphoma are deficient in EBNA1‐specific IFN‐γ T cell responses

Abstract

Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in equatorial Africa and is linked to Epstein-Barr virus (EBV) and Plasmodium falciparum coinfections early in life. Epstein-Barr nuclear antigen 1 (EBNA1) is the sole viral latent antigen expressed in BL tumors. Loss of EBNA1-specific immune surveillance could allow eBL emergence. Therefore, EBNA1-specific T cell responses were analyzed by IFN-c ELISPOT in Kenyan children with eBL and compared to healthy children with divergent malaria exposure. Significantly fewer children with eBL, 16% (7/44) had EBNA1-specific IFN-c responses in contrast to healthy children living in a malaria holoendemic area or in an area with sporadic malaria transmission, 67% (40/60) and 72% (43/60) responders, respectively (p < 0.003). Children with eBL maintained IgG 1 dominated antibody responses to EBNA1 similar to healthy children suggesting a selective loss of IFN-c secreting EBNA1-specific T cells in the presence of intact humoral immunity. CD81 T cell responses to EBV lytic and latent antigens not expressed in the tumors were similarly robust in eBL patients compared to healthy children. In addition, CD41 T cell responses to a malaria protein, merozoite surface protein 1, were present in lymphoma patients. This study demonstrates a selective loss of EBNA1-specific T cell responses in children with eBL and suggests a potential immunotherapeutic target for this EBV-associated lymphoma. '

Holoendemic Malaria Exposure Is Associated with Altered Epstein-Barr Virus-Specific CD8 + T-Cell Differentiation

“…Our data demonstrate that EBV-specific, but not CMV-specific or total, CD8 ϩ T-cell populations show significant differences associated with malaria exposure. These findings are consistent with previous studies showing that T-cell responses to malaria antigens and nonspecific mitogens are equally robust across study populations and age groups (46). Thus, malaria exposure uniquely impacts the EBV-specific CD8 ϩ T-cell compartment, which argues against a role for generalized immune suppression in the pathogenesis of eBL.…”

“…For these reasons, we used a sophisticated flow cytometric approach optimized for rare event analysis to demonstrate that a loss of central memory-like EBV-specific CD8 ϩ T cells is associated with malaria exposure. Such immunologic perturbations within the EBV-specific CD8 ϩ T-cell compartment could predispose to the functional deficits that accompany eBL (46). Second, our study addresses the long-standing question of whether eBL is associated with a generalized, malaria-induced suppression of T-cell immunity (21,22,47).…”

The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV-related disorders

“…The immunological control exerted by EBNA1-specific CD4 + is crucial, since a loss of this response was recently demonstrated in patients with EBV-associated lymphomas, 103 and children with Burkitt's lymphoma. 104 These findings, together with the fact that EBNA1 expression is associated with all types of EBV latency and generally does not induce an important CD8 + T-cell response, suggest, in principle, a primary role for EBNA1-specific CD4 + T-cell lines in adoptive T-cell therapy for all EBV-related tumors, irrespective of the latency phenotype.…”

CD4+and CD8+T-Cell Responses to Latent Antigen EBNA-1 and Lytic Antigen BZLF-1 during Persistent Lymphocryptovirus Infection of Rhesus Macaques

“…Additionally, EBNA-1 is an immunodominant target of EBV-specific CD4 ϩ T cells that are capable of inhibiting virus-induced B-cell proliferation in vitro (17,18). In support of the importance of EBNA-1-specific T-cell responses, loss of EBNA-1-specific CD4 ϩ or CD8 ϩ T cells has been correlated with numerous diseases, including non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and Burkitt's lymphoma (19)(20)(21)(22)(23).…”