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

Abstract

e Coinfection with Plasmodium falciparum malaria and Epstein-Barr virus (EBV) is a major risk factor for endemic Burkitt lymphoma (eBL), still one of the most prevalent pediatric cancers in equatorial Africa. Although malaria infection has been associated with immunosuppression, the precise mechanisms that contribute to EBV-associated lymphomagenesis remain unclear. In this study, we used polychromatic flow cytometry to characterize CD8 ؉ T-cell subsets specific for EBV-derived lytic (BMFL1 and BRLF1) and latent (LMP1, LMP2, and EBNA3C) antigens in individuals with divergent malaria exposure. No malaria-associated differences in EBV-specific CD8 ؉ T-cell frequencies were observed. However, based on a multidimensional analysis of CD45RO, CD27, CCR7, CD127, CD57, and PD-1 expression, we found that individuals living in regions with intense and perennial (holoendemic) malaria transmission harbored more differentiated EBV-specific CD8 ؉ T-cell populations that contained fewer central memory cells than individuals living in regions with little or no (hypoendemic) malaria. This profile shift was most marked for EBV-specific CD8؉ T-cell populations that targeted latent antigens. Importantly, malaria exposure did not skew the phenotypic properties of either cytomegalovirus (CMV)-specific CD8 ؉ T cells or the global CD8 ؉ memory T-cell pool. These observations define a malaria-associated aberration localized to the EBV-specific CD8 ؉ T-cell compartment that illuminates the etiology of eBL.

β-Cell–Specific CD8 T Cell Phenotype in Type 1 Diabetes Reflects Chronic Autoantigen Exposure

“…+ population of b-cell-specific CD8 T cells in type 1 diabetic patients that was significantly less frequent in healthy control subjects, again consistent with an antigen-driven disease process as reported previously in a viral system (43). Importantly, all three analytical approaches yielded significant differences between subject groups solely within the b-cell-specific CD8 T cell compartment.…”

T-Cell Responses to EBV

“…Studies of children in high-and lowincidence malaria areas show the former have high EBV viral loads (Moormann et al 2005). Subsequent studies have shown that children living in endemic malarial areas have reduced CD8 T-cell responses to EBV lytic and latent antigens (Moormann et al 2007) or phenotypic changes in these responses consistent with greater differentiation (Chattopadhyay et al 2013); each could conceivably alter the virus-host balance to favour the development of Burkitt lymphoma. An alterative, but not necessarily mutually exclusive explanation for the development of Burkitt lymphoma is that the tumours are able to develop because they escape immune control.…”

Burkitt’s Lymphoma

“…In addition, non-BL, malaria-exposed children lacking IFN-γ responses to EBNA-1 had higher median EBV loads compared to healthy children with EBNA1-specific T-cell immunity. Another study by Chattopadhyay et al used HLA-A2 tetramers to phenotype CD8+ T cells specific to EBV lytic (BMFL1 and BRLF1) and latent (LMP1, LMP2, and EBNA3C) peptides and multidimensional analysis of CD45RO, CD27, CCR7, CD127, CD57, and PD-1 expression (Chattopadhyay et al 2013). They found that CD8+ T cells against lytic antigens tended to display an exhausted phenotype lacking homeostatic potential and individuals residing in malaria holoendemic areas had more differentiated CD8+ T cells to EBV latent antigens with fewer central memory subsets compared to those living in regions with little to no malaria transmission.…”