@article{ecee5d02fb744bf6ac546396159b6901,
title = "Defects in Antiviral T Cell Responses Inflicted by Aging-Associated miR-181a Deficiency",
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.",
keywords = "CD8 effector T cell, T cell repertoire, antiviral response, immune aging, immunosenescence, microRNA",
author = "Chulwoo Kim and Jadhav, {Rohit R.} and Gustafson, {Claire E.} and Smithey, {Megan J.} and Hirsch, {Alec J.} and Uhrlaub, {Jennifer L.} and Hildebrand, {William H.} and Janko Nikolich-{\v Z}ugich and Weyand, {Cornelia M.} and Goronzy, {J{\"o}rg J.}",
note = "Funding Information: We thank Dr. C.Z. Chen (Stanford University) for generously providing miR-181ab1 fl/fl mice and Dr. R. Ahmed (Emory University) and Dr. S. Hale (University of Utah) for providing SMARTA mice and LCMV-Armstrong and Lm-gp61 constructs. We thank Y.S. Choi (Seoul National University, South Korea) for LMPd-Ametrine vector and the NIH tetramer core facility (Atlanta, GA) for providing tetramers. This work was supported by the National Institutes of Health ( NIH ) ( R01 AI108891 , R01 AG045779 , U19 AI057266 , R01 AI129191 to J.J.G.; R01 AR042527 , R01 HL117913 , R01 AI108906 , and P01 HL129941 to C.M.W.; and N01 AI00017 to J.N.-{\v Z}.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: We thank Dr. C.Z. Chen (Stanford University) for generously providing miR-181ab1fl/fl mice and Dr. R. Ahmed (Emory University) and Dr. S. Hale (University of Utah) for providing SMARTA mice and LCMV-Armstrong and Lm-gp61 constructs. We thank Y.S. Choi (Seoul National University, South Korea) for LMPd-Ametrine vector and the NIH tetramer core facility (Atlanta, GA) for providing tetramers. This work was supported by the National Institutes of Health (NIH) (R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191 to J.J.G.; R01 AR042527, R01 HL117913, R01 AI108906, and P01 HL129941 to C.M.W.; and N01 AI00017 to J.N.-?.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. C.K. C.M.W. and J.J.G. designed and analyzed the experiments. M.J.S. J.L.U. and J.N.-?. assembled the cohort of WNV-immune individuals, and W.H.H. genotyped HLA. C.K. and A.J.H. performed the experiments. TCR repertoire studies were done by C.K. C.E.G. and R.R.J. C.K. and J.J.G. wrote the manuscript with all authors providing feedback. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = nov,
day = "19",
doi = "10.1016/j.celrep.2019.10.044",
language = "English (US)",
volume = "29",
pages = "2202--2216.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}