Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection
- 16 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Immunology
- Vol. 21 (4), 434-441
- https://doi.org/10.1038/s41590-020-0628-2
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.Funding Information
- Deutsche Forschungsgemeinschaft (SFB 1321/TP17, SFB 1054/B09, SFB 1371/TP04, FOR2830/TP5, SFB 1054/B09)
This publication has 60 references indexed in Scilit:
- Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissueCancer Immunology, Immunotherapy, 2013
- MHC Multimer-Guided and Cell Culture-Independent Isolation of Functional T Cell Receptors from Single Cells Facilitates TCR Identification for ImmunotherapyPLOS ONE, 2013
- Functional Avidity: A Measure to Predict the Efficacy of Effector T Cells?Journal of Immunology Research, 2012
- Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infectionThe Journal of Experimental Medicine, 2012
- T Cell Receptor αβ Diversity Inversely Correlates with Pathogen-Specific Antibody Levels in Human Cytomegalovirus InfectionScience Translational Medicine, 2012
- Complete but curtailed T-cell response to very low-affinity antigenNature, 2009
- Endogenous Naive CD8+ T Cell Precursor Frequency Regulates Primary and Memory Responses to InfectionImmunity, 2008
- Naive CD4+ T Cell Frequency Varies for Different Epitopes and Predicts Repertoire Diversity and Response MagnitudeImmunity, 2007
- Selective Depletion of High-Avidity Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8 + T Cells after Early HIV-1 InfectionJournal of Virology, 2007
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005