Schober and Voit et al. showed that the most numerous human and mouse CMV-specific CD8+ T cell populations are biased to low TCR affinity. Analyses of endogenous and transferred CD8+ T cells of distinct affinities showed that during acute murine infection, CMV-specific, high-affinity TCRs diversified and stabilized, and then low-affinity clonotypes began to dominate. High-affinity CD8+ T cells expressed differentiation and activation genes, which waned, and a differentiated, senescent (not exhausted) phenotype emerged. The low-affinity CD8+ T cell clones that dominated during latency expressed memory or predicted T cell response repressor genes.
Contributed by Paula Hochman
ABSTRACT: Adaptive evolution is a key feature of T cell immunity. During acute immune responses, T cells harboring high-affinity T cell antigen receptors (TCRs) are preferentially expanded, but whether affinity maturation by clonal selection continues through the course of chronic infections remains unresolved. Here we investigated the evolution of the TCR repertoire and its affinity during the course of infection with cytomegalovirus, which elicits large T cell populations in humans and mice. Using single-cell and bulk TCR sequencing and structural affinity analyses of cytomegalovirus-specific T cells, and through the generation and in vivo monitoring of defined TCR repertoires, we found that the immunodominance of high-affinity T cell clones declined during the chronic infection phase, likely due to cellular senescence. These data showed that under conditions of chronic antigen exposure, low-affinity TCRs preferentially expanded within the TCR repertoire, with implications for immunotherapeutic strategies.
Author Info: (1) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. kilian.schober@tum.de. (2) Institute for Medical Microbiology
Author Info: (1) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. kilian.schober@tum.de. (2) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (3) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (4) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. (5) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (6) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (7) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (8) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (9) Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany. (10) ENPICOM B.V., 's-Hertogenbosch, the Netherlands. (11) ENPICOM B.V., 's-Hertogenbosch, the Netherlands. (12) Juno Therapeutics/Celgene, Seattle, WA, USA. (13) Juno Therapeutics/Celgene, Seattle, WA, USA. (14) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (15) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (16) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (17) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (18) Institute for Immunology, Ludwig-Maximilians-Universitat, Munich, Germany. (19) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (20) Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany. (21) German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany. Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany. (22) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. (23) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen (TUM), Munich, Germany. dirk.busch@tum.de. German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany. dirk.busch@tum.de. Focus Group 'Clinical Cell Processing and Purification', Institute for Advanced Study, TUM, Munich, Germany. dirk.busch@tum.de.
