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Principal Investigator: Nan-ping Peter Weng
Organization: NATIONAL INSTITUTE ON AGING
Fiscal Year: 2024
Award: $444,588
Funding agency: National Institute on Aging
A vast array of T cell receptors (TCRs) is generated during T cell development in the thymus through V(D)J recombination, which involves the rearrangement of multiple V, D, and J genes and the pairing of and chains. These diverse TCRs provide protection to the human body against a multitude of foreign pathogens and internal cancer cells. The entirety of TCRs present in an individual's T cells is referred to as the TCR repertoire. Despite an estimated 4 x 10^11 T cells in the adult human body, the lower bound estimate for the TCR repertoire is 3.8 x 10^8. While the number of circulating T cells may slightly decrease with age, the changes in the diversity of the TCR repertoire is more apparent. Alterations of TCR repertoire with age were observed in all four subsets of T cells. The greatest reduction was observed in nave CD8+ T cells; the greatest clonal expansion was in memory CD8+ T cells, and the highest increased retention of TCR sequences was in memory CD8+ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8+ than CD4+ T cells, suggesting aging has a more profound impact on the cytotoxic than on the helper T cell functions. This may explain the increased susceptibility of older adults to the novel infections.
The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8+ T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8+ T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here, we analyzed CD8+ T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein and found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8+ T cells but significantly enhanced activation-induced proliferation compared to that of the uninfected donors. The frequencies of N-specific CD8+ T cells and their proliferative response to stimulation did not decrease over one year. We identified the N222-230 peptide (LLLDRLNQL, referred to as LLL thereafter) as a dominant epitope that elicited the greatest proliferative response from both convalescent and uninfected donors. Single-cell sequencing of T cell receptors (TCR) from LLL-specific CD8+ T cells revealed highly restricted V-alpha gene usage (TRAV12-2) with limited CDR3-alpha motifs, supported by structural characterization of the TCR–LLL–HLA-A2 complex. Lastly, transcriptome analysis of LLL-specific CD8+ T cells from donors who had expansion (expanders) or no expansion (non-expanders) after in vitro stimulation identified increased chromatin modification and innate immune functions of CD8+ T cells in non-expanders. These results suggests that SARS-CoV-2 infection induces LLL-specific CD8+ T cell responses with a restricted TCR repertoire.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Adult><Adult Human><Age><Aging><Antigenic Determinants><Antigens><Binding><Binding Determinants><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CMV><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><Cell Function><Cell Mediated Immunology><Cell Physiology><Cell Process><Cell-Mediated Immunity><Cellular Function><Cellular Immunity><Cellular Physiology><Cellular Process><Clonal Expansion><CoV-2><CoV2><Complex><Cytomegalovirus><Disease><Disorder><Epitopes><Frequencies><Genes><Goals><HCMV><HLA Class I Histocompatibility Antigen, A-2 Alpha Chain><HLA-A Class I Antigen 2><HLA-A Histocompatibility Type Antigen 2><HLA-A2><HLA-A2 Antigen><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Human Figure><Human body><Immunity><Immunoglobulin V(D)J Rearrangement><In Vitro><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Influenza Virus><LYT3><MHC Receptor><Major Histocompatibility Complex Receptor><Major Histocompatibility Complex, Class I, A2 Antigen><Malignant Cell><Measures><Memory><Methods><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Nucleocapsid><Peptides><Play><Predisposition><Proliferating><Proteins><Receptors, Antigen, T-Cell, alpha-beta><Resolution><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Salivary Gland Viruses><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Single cell seq><Subcellular Process><Susceptibility><T cell response><T-Cell Antigen Receptor Specificity><T-Cell Antigen Receptors><T-Cell Development><T-Cell Ontogeny><T-Cell Receptor><T-Cell Receptor Specificity><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Development><T-Lymphocyte Subsets><T-cell diversity><T-cell receptor repertoire><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TCR repertoire><TcR alpha-beta><TcR αβ><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><V(D)J Rearrangement><V(D)J Recombination><VDJ rearrangement><VDJ recombination><Wuhan coronavirus><adulthood><age associated><age associated alterations><age associated changes><age associated effects><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age effect><age linked><age related><age related alterations><age related changes><age related effects><age specific><age specific alterations><age specific changes><ages><aging effect><alpha-beta T-Cell Receptor><alterations with age><antigen-specific T cells><cancer cell><changes with age><chromatin modification><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytomegalovirus group><cytotoxic><global gene expression><global transcription profile><hCoV19><immunogen><impact of age><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><influence of age><influenzavirus><innate immune function><nCoV2><novel><older adult><older adulthood><pathogen><precision medicine><precision-based medicine><resolutions><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell next generation sequencing><single cell sequencing><single cell transcriptomic profiling><single-cell RNA sequencing><social role><thymus derived lymphocyte><transcriptome><αβ T-Cell Receptor>