Interplay between IL-10, IFN-gamma, IL-17A and PD-1 Expressing EBNA1-Specific CD4(+) and CD8(+) T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma
Mulama, David H.
Saikumar Lakshmi, Priya
Otieno, Juliana A.
Kurtis, Jonathan D.
Berg, Leslie J.
Ong'echa, John M.
Moormann, Ann M.
UMass Chan AffiliationsDivision of Infectious Diseases and Immunology, Department of Medicine
endemic Burkitt lymphoma
Immunology and Infectious Disease
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AbstractChildren diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-gamma (IFN-gamma) responses to Epstein-Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific T cells have not been characterized for eBL. Using a bespoke flow cytometry assay we measured intracellular IFN-gamma, IL-10, IL-17A expression and phenotyped CD4(+) and CD8(+) T cell effector memory subsets specific to EBNA1 for eBL patients compared to two groups of healthy children with divergent malaria exposures. In response to EBNA1 and a malaria antigen (PfSEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-gamma-producing CD4(+) T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (p < 0.0001 and p = 0.0004, respectively). However, eBL patients did not differ in CD8(+) T cell response rates or the magnitude of IFN-gamma expression. In contrast, eBL children were more likely to have EBNA1-specific CD4(+) T cells expressing IL-10, and less likely to have polyfunctional IFN-gamma(+)IL-10(+) CD4(+) T cells (p = 0.02). They were also more likely to have IFN-gamma(+)IL-17A(+), IFN-gamma(+) and IL-17A(+) CD8(+) T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA(+)CCR7(+) TNAIVE-LIKE cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (TCM) and effector memory (TEM) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-gamma(+) EBNA1-specific CD4(+) T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis.
Forconi CS, Mulama DH, Saikumar Lakshmi P, Foley J, Otieno JA, Kurtis JD, Berg LJ, Ong'echa JM, Münz C, Moormann AM. Interplay between IL-10, IFN-γ, IL-17A and PD-1 Expressing EBNA1-Specific CD4+ and CD8+ T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma. Cancers (Basel). 2021 Oct 27;13(21):5375. doi: 10.3390/cancers13215375. PMID: 34771539; PMCID: PMC8582526. Link to article on publisher's site