Heterogeneity of human anti-viral immunity shaped by virus, tissue, age, and sex

Cell Rep. 2021 Nov 30;37(9):110071. doi: 10.1016/j.celrep.2021.110071.


The persistence of anti-viral immunity is essential for protection and exhibits profound heterogeneity across individuals. Here, we elucidate the factors that shape maintenance and function of anti-viral T cell immunity in the body by comprehensive profiling of virus-specific T cells across blood, lymphoid organs, and mucosal tissues of organ donors. We use flow cytometry, T cell receptor sequencing, single-cell transcriptomics, and cytokine analysis to profile virus-specific CD8+ T cells recognizing the ubiquitous pathogens influenza and cytomegalovirus. Our results reveal that virus specificity determines overall magnitude, tissue distribution, differentiation, and clonal repertoire of virus-specific T cells. Age and sex influence T cell differentiation and dissemination in tissues, while T cell tissue residence and functionality are highly correlated with the site. Together, our results demonstrate how the covariates of virus, tissue, age, and sex impact the anti-viral immune response, which is important for targeting, monitoring, and predicting immune responses to existing and emerging viruses.

Keywords: T lymphocytes; anti-viral immunity; cytomegalovirus; human immunology; immunological memory; influenza; lymphoid organs; mucosal immunity; tissue resident memory T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Age Factors
  • Antiviral Agents / pharmacology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Child
  • Child, Preschool
  • Cytokines / metabolism
  • Cytomegalovirus / immunology*
  • Cytomegalovirus Infections / drug therapy
  • Cytomegalovirus Infections / immunology*
  • Cytomegalovirus Infections / virology
  • Female
  • Humans
  • Immunologic Memory / immunology*
  • Infant
  • Influenza A virus / immunology*
  • Influenza, Human / drug therapy
  • Influenza, Human / immunology*
  • Influenza, Human / virology
  • Lymphocyte Activation
  • Male
  • Receptors, Antigen, T-Cell / immunology
  • Sex Factors
  • Single-Cell Analysis
  • Transcriptome


  • Antiviral Agents
  • Cytokines
  • Receptors, Antigen, T-Cell