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:	Catherine S. Forconi, David H. Mulama, Priya Saikumar Lakshmi, Joslyn Foley, Juliana A. Otieno, Jonathan D. Kurtis, Leslie J. Berg, John M. Ong’echa, Christian Münz, Ann M. Moormann
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	endemic Burkitt lymphoma EBV T-cells EBNA1 cytokines PD-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/bb122935afb24a43bdd53e3e655ec679
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spelling	oai:doaj.org-article:bb122935afb24a43bdd53e3e655ec6792021-11-11T15:29:33ZInterplay 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 Lymphoma10.3390/cancers132153752072-6694https://doaj.org/article/bb122935afb24a43bdd53e3e655ec6792021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5375https://doaj.org/toc/2072-6694Children 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.Catherine S. ForconiDavid H. MulamaPriya Saikumar LakshmiJoslyn FoleyJuliana A. OtienoJonathan D. KurtisLeslie J. BergJohn M. Ong’echaChristian MünzAnn M. MoormannMDPI AGarticleendemic Burkitt lymphomaEBVT-cellsEBNA1cytokinesPD-1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5375, p 5375 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	endemic Burkitt lymphoma EBV T-cells EBNA1 cytokines PD-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	endemic Burkitt lymphoma EBV T-cells EBNA1 cytokines PD-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Catherine S. Forconi David H. Mulama Priya Saikumar Lakshmi Joslyn Foley Juliana A. Otieno Jonathan D. Kurtis Leslie J. Berg John M. Ong’echa Christian Münz Ann M. Moormann 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
description	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.
format	article
author	Catherine S. Forconi David H. Mulama Priya Saikumar Lakshmi Joslyn Foley Juliana A. Otieno Jonathan D. Kurtis Leslie J. Berg John M. Ong’echa Christian Münz Ann M. Moormann
author_facet	Catherine S. Forconi David H. Mulama Priya Saikumar Lakshmi Joslyn Foley Juliana A. Otieno Jonathan D. Kurtis Leslie J. Berg John M. Ong’echa Christian Münz Ann M. Moormann
author_sort	Catherine S. Forconi
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bb122935afb24a43bdd53e3e655ec679
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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

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