Individual Epitope-Specific CD8+ T Cell Immune Responses Are Shaped Differently during Chronic Viral Infection

Sebastian Klein; Jasmin Mischke; Finn Beruldsen; Immo Prinz; Dinler A Antunes; Markus Cornberg; Anke R M Kraft

doi:10.3390/pathogens12050716

Individual Epitope-Specific CD8⁺ T Cell Immune Responses Are Shaped Differently during Chronic Viral Infection

Pathogens. 2023 May 14;12(5):716. doi: 10.3390/pathogens12050716.

Authors

Sebastian Klein^{1

2}, Jasmin Mischke^{1

2}, Finn Beruldsen³, Immo Prinz^{4

5}, Dinler A Antunes³, Markus Cornberg^{1

2

6

7}, Anke R M Kraft^{1

2

6

7}

Affiliations

¹ Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
² Twincore Centre for Experimental and Clinical Infection Medicine, 30625 Hannover, Germany.
³ Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
⁴ Institute of Systems Immunology, University Medical Center Eppendorf, 20251 Hamburg, Germany.
⁵ Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany.
⁶ German Centre for Infection Research (DZIF), 30625 Hannover, Germany.
⁷ Centre for Individualised Infection Medicine (CIIM), c/o CRC Hannover, 30625 Hannover, Germany.

Abstract

A hallmark in chronic viral infections are exhausted antigen-specific CD8⁺ T cell responses and the inability of the immune system to eliminate the virus. Currently, there is limited information on the variability of epitope-specific T cell exhaustion within one immune response and the relevance to the T cell receptor (TCR) repertoire. The aim of this study was a comprehensive analysis and comparison of three lymphocytic choriomeningitis virus (LCMV) epitope-specific CD8⁺ T cell responses (NP396, GP33 and NP205) in a chronic setting with immune intervention, e.g., immune checkpoint inhibitor (ICI) therapy, in regard to the TCR repertoire. These responses, though measured within the same mice, were individual and independent from each other. The massively exhausted NP396-specific CD8⁺ T cells revealed a significantly reduced TCR repertoire diversity, whereas less-exhausted GP33-specific CD8⁺ T cell responses were rather unaffected by chronicity in regard to their TCR repertoire diversity. NP205-specific CD8⁺ T cell responses showed a very special TCR repertoire with a prominent public motif of TCR clonotypes that was present in all NP205-specific responses, which separated this from NP396- and GP33-specific responses. Additionally, we showed that TCR repertoire shifts induced by ICI therapy are heterogeneous on the epitope level, by revealing profound effects in NP396-, less severe and opposed effects in NP205-, and minor effects in GP33-specific responses. Overall, our data revealed individual epitope-specific responses within one viral response that are differently affected by exhaustion and ICI therapy. These individual shapings of epitope-specific T cell responses and their TCR repertoires in an LCMV mouse model indicates important implications for focusing on epitope-specific responses in future evaluations for therapeutic approaches, e.g., for chronic hepatitis virus infections in humans.

Keywords: CD8+ T cells; T cell receptor repertoire; checkpoint inhibitor therapy; chronic viral infection; lymphocytic choriomeningitis virus.

Grants and funding

KR 2913/2-1/Deutsche Forschungsgemeinschaft