Defects in Antiviral T Cell Responses Inflicted by Aging-Associated miR-181a Deficiency

Chulwoo Kim, Rohit R. Jadhav, Claire E. Gustafson, Megan J. Smithey, Alec J. Hirsch, Jennifer L. Uhrlaub, William H. Hildebrand, Janko Nikolich-Žugich, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticle

Abstract

Generation of protective immunity to infections and vaccinations declines with age. Studies in healthy individuals have implicated reduced miR-181a expression in T cells as contributing to this defect. To understand the impact of miR-181a expression on antiviral responses, we examined LCMV infection in mice with miR-181ab1-deficient T cells. We found that miR-181a deficiency delays viral clearance, thereby biasing the immune response in favor of CD4 over CD8 T cells. Antigen-specific CD4 T cells in mice with miR-181a-deficient T cells expand more and have a broader TCR repertoire with preferential expansion of high-affinity T cells than in wild-type mice. Importantly, generation of antigen-specific miR-181a-deficient CD8 effector T cells is particularly impaired, resulting in lower frequencies of CD8 T cells in the liver even at time points when the infection has been cleared. Consistent with the mouse model, CD4 memory T cells in individuals infected with West Nile virus at older ages tend to be more frequent and of higher affinity. T cell aging in humans is associated with progressive loss in miR-181a, the implications of which for antiviral immunity are unknown. Using mouse models, Kim et al. find that miR-181a deficiency in T cells reproduces many aging features including impaired effector T cell expansion, viral clearance, generation of tissue-residing T cells, and recall responses.

Original languageEnglish (US)
Pages (from-to)2202-2216.e5
JournalCell Reports
Volume29
Issue number8
DOIs
Publication statusPublished - Nov 19 2019

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Keywords

  • antiviral response
  • CD8 effector T cell
  • immune aging
  • immunosenescence
  • microRNA
  • T cell repertoire

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kim, C., Jadhav, R. R., Gustafson, C. E., Smithey, M. J., Hirsch, A. J., Uhrlaub, J. L., ... Goronzy, J. J. (2019). Defects in Antiviral T Cell Responses Inflicted by Aging-Associated miR-181a Deficiency. Cell Reports, 29(8), 2202-2216.e5. https://doi.org/10.1016/j.celrep.2019.10.044