Interplay between IL-10, IFN-γ, IL-17A and PD-1 Expressing EBNA1-Specific CD4<sup>+</sup> and CD8<sup>+</sup> T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma
Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) 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...
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| Autores principales: | , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/bb122935afb24a43bdd53e3e655ec679 |
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| Sumario: | Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) 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-γ, IL-10, IL-17A expression and phenotyped CD4<sup>+</sup> and CD8<sup>+</sup> 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 (<i>Pf</i>SEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-γ-producing CD4<sup>+</sup> T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (<i>p</i> < 0.0001 and <i>p</i> = 0.0004, respectively). However, eBL patients did not differ in CD8<sup>+</sup> T cell response rates or the magnitude of IFN-γ expression. In contrast, eBL children were more likely to have EBNA1-specific CD4<sup>+</sup> T cells expressing IL-10, and less likely to have polyfunctional IFN-γ<sup>+</sup>IL-10<sup>+</sup> CD4<sup>+</sup> T cells (<i>p</i> = 0.02). They were also more likely to have IFN-γ<sup>+</sup>IL-17A<sup>+</sup>, IFN-γ<sup>+</sup> and IL-17A<sup>+</sup> CD8<sup>+</sup> T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA<sup>+</sup>CCR7<sup>+</sup> T<sub>NAIVE-LIKE</sub> cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (T<sub>CM</sub>) and effector memory (T<sub>EM</sub>) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-γ<sup>+</sup> EBNA1-specific CD4<sup>+</sup> T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis. |
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