TY - JOUR
T1 - Human mucosal-associated invariant t cells in older individuals display expanded tcrαβ clonotypes with potent antimicrobial responses
AU - Loh, Liyen
AU - Gherardin, Nicholas A.
AU - Sant, Sneha
AU - Grzelak, Ludivine
AU - Crawford, Jeremy Chase
AU - Bird, Nicola L.
AU - Koay, Hui Fern
AU - Van De Sandt, Carolien E.
AU - Moreira, Marcela L.
AU - Lappas, Martha
AU - Allen, E. Kaitlynn
AU - Crowe, Jane
AU - Loudovaris, Thomas
AU - Flanagan, Katie L.
AU - Quinn, Kylie M.
AU - Rossjohn, Jamie
AU - Thomas, Paul G.
AU - Eckle, Sidonia B.G.
AU - McCluskey, James
AU - Godfrey, Dale I.
AU - Kedzierska, Katherine
N1 - Funding Information:
This work was supported by National Health and Medical Research Council (NHMRC) Program Grant 1071916 (to K.K.), Program Grant 1113293 (to D.I.G.), and Project Grant 1140126 (to D.I.G.) and the Australian Research Council (ARC) (CE140100011). H.-F.K. is supported by an NHMRC Early Career Fellowship (1160333). K.K. is an NHMRC Senior Research Fellow (1102792), D.I.G. is supported by an NHMRC Senior Principal Research Fellowship (1117766), J.R. is an ARC Australian Laureate Fellow, and S.S. was supported by the Victoria India Doctoral Scholarship and The University of Melbourne International Fee Remission Scholarship. S.B.G.E. is an ARC Discovery Early Career Researcher Award Fellow (DE170100407). M.L. is supported by a research fellowship from the Department of Obstetrics and Gynaecology (The University of Melbourne) and a faculty fellowship from The University of Melbourne. C.E.v.d.S. has received funding from the European Union Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie Grant Agreement 792532. K.L.F. was awarded funding from The Clifford Craig Foundation.
Publisher Copyright:
© 2020 by The American Association of Immunologists, Inc.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT cells are altered during different phases across the human life span is largely unknown. Although also abundant in the tissues, our study focuses on MAIT cell analyses in blood. Across the human life span, we show that naive-like MAIT cells in umbilical cord blood switch to a central/effector memory-like profile that is sustained into older age. Whereas low-γrade levels of plasma cytokine/chemokine were apparent in older donors (>65 y old), surprisingly, they did not correlate with the ex vivo MAIT hyperinflammatory cytokine profile observed in older adults. Removal of MAIT cells from older individuals and an aged environment resulted in the reversal of the baseline effector molecule profile compaRαβle with MAIT cells from younger adults. An upregulated basal inflammatory profile accounted for reduced Escherichia coli-specific responses in aged MAIT cells compared with their young adult counterparts when fold change in expression levels of GzmB, CD107a, IFN-γ, and TNF was examined. However, the magnitude of antimicrobial MR1-dependent activation remained as potent and polyfunctional as with younger adults. Paired TCRαβ analyses of MAIT cells revealed large clonal expansions in older adults and tissues that rivalled, remarkably, the TCRαβ repertoire diversity of virus-specific CD8+ T cells. These data suggest that MAIT cells in older individuals, although associated with large clonal TCRαβ expansions and increased baseline inflammatory potential, demonstrate plasticity and provide potent antimicrobial immunity.
AB - Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT cells are altered during different phases across the human life span is largely unknown. Although also abundant in the tissues, our study focuses on MAIT cell analyses in blood. Across the human life span, we show that naive-like MAIT cells in umbilical cord blood switch to a central/effector memory-like profile that is sustained into older age. Whereas low-γrade levels of plasma cytokine/chemokine were apparent in older donors (>65 y old), surprisingly, they did not correlate with the ex vivo MAIT hyperinflammatory cytokine profile observed in older adults. Removal of MAIT cells from older individuals and an aged environment resulted in the reversal of the baseline effector molecule profile compaRαβle with MAIT cells from younger adults. An upregulated basal inflammatory profile accounted for reduced Escherichia coli-specific responses in aged MAIT cells compared with their young adult counterparts when fold change in expression levels of GzmB, CD107a, IFN-γ, and TNF was examined. However, the magnitude of antimicrobial MR1-dependent activation remained as potent and polyfunctional as with younger adults. Paired TCRαβ analyses of MAIT cells revealed large clonal expansions in older adults and tissues that rivalled, remarkably, the TCRαβ repertoire diversity of virus-specific CD8+ T cells. These data suggest that MAIT cells in older individuals, although associated with large clonal TCRαβ expansions and increased baseline inflammatory potential, demonstrate plasticity and provide potent antimicrobial immunity.
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U2 - 10.4049/jimmunol.1900774
DO - 10.4049/jimmunol.1900774
M3 - Article
C2 - 31988181
AN - SCOPUS:85079850943
VL - 204
SP - 1119
EP - 1133
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 5
ER -