UMMS Affiliation

Division of Infectious Diseases and Immunology, Department of Medicine

Publication Date

2021-10-27

Document Type

Article

Disciplines

Cancer Biology | Immunology and Infectious Disease | Neoplasms | Pediatrics | Virus Diseases

Abstract

Children 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.

Keywords

EBNA1, EBV, Kenya, PD-1, T-cells, cytokines, endemic Burkitt lymphoma, malaria

Rights and Permissions

Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

DOI of Published Version

10.3390/cancers13215375

Source

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

Journal/Book/Conference Title

Cancers

Related Resources

Link to Article in PubMed

PubMed ID

34771539

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Share

COinS