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High MDR‐1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR‐1 substrates
High expression of the ATP‐binding cassette‐multi‐drug efflux protein 1 (MDR1) is a striking feature of mucosal‐associated invariant T (MAIT) cells, a prominent human innate‐like T cell subset. We demonstrate significantly higher MDR1 expression by CD8 (+) CD161 (++) Vα7.2 (+) MAIT cells than the ph...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194332/ https://www.ncbi.nlm.nih.gov/pubmed/30231297 http://dx.doi.org/10.1111/cei.13165 |
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author | Fergusson, J.R. Ussher, J.E. Kurioka, A. Klenerman, P. Walker, L.J. |
author_facet | Fergusson, J.R. Ussher, J.E. Kurioka, A. Klenerman, P. Walker, L.J. |
author_sort | Fergusson, J.R. |
collection | PubMed |
description | High expression of the ATP‐binding cassette‐multi‐drug efflux protein 1 (MDR1) is a striking feature of mucosal‐associated invariant T (MAIT) cells, a prominent human innate‐like T cell subset. We demonstrate significantly higher MDR1 expression by CD8 (+) CD161 (++) Vα7.2 (+) MAIT cells than the phenotypically and functionally related CD8 (+) CD161 (++) Vα7.2‐subset and show MDR1 expression to be similarly high throughout MAIT CD4(+) , CD8(+) , double‐negative (DN) and double‐positive (DP) cell subsets. We demonstrate the MAIT cell‐predominant CD8(+)CD161(++) subset to uniquely and efficiently efflux the cytotoxic anthracycline daunorubicin, retain function on daunorubicin exposure and demonstrate MDR1‐dependent protection from daunorubicin‐induced apoptosis. By contrast, CD8(+)CD161(++)Vα7.2(+) MAIT cells were not protected from the anti‐proliferative and cytotoxic effects of the immunosuppressive MDR1 substrates tacrolimus and mycophenoic acid, although function following MAIT cell‐specific T cell receptor (TCR)‐dependent and ‐independent stimulation was preserved on in‐vitro exposure to these agents. Overall, our data further define MDR1 expression by CD161(++) T and MAIT cells and demonstrate the potential for high MDR1 expression by MAIT cells to confer resistance to cytotoxic MDR1 substrates in vivo . As our understanding of the importance of MAIT cells in human immunity and immunopathology grows, this is an important observation for clinical contexts such as the treatment of malignancy, autoimmunity and post‐transplant immunosuppression. |
format | Online Article Text |
id | pubmed-6194332 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61943322018-10-30 High MDR‐1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR‐1 substrates Fergusson, J.R. Ussher, J.E. Kurioka, A. Klenerman, P. Walker, L.J. Clin Exp Immunol Original Articles High expression of the ATP‐binding cassette‐multi‐drug efflux protein 1 (MDR1) is a striking feature of mucosal‐associated invariant T (MAIT) cells, a prominent human innate‐like T cell subset. We demonstrate significantly higher MDR1 expression by CD8 (+) CD161 (++) Vα7.2 (+) MAIT cells than the phenotypically and functionally related CD8 (+) CD161 (++) Vα7.2‐subset and show MDR1 expression to be similarly high throughout MAIT CD4(+) , CD8(+) , double‐negative (DN) and double‐positive (DP) cell subsets. We demonstrate the MAIT cell‐predominant CD8(+)CD161(++) subset to uniquely and efficiently efflux the cytotoxic anthracycline daunorubicin, retain function on daunorubicin exposure and demonstrate MDR1‐dependent protection from daunorubicin‐induced apoptosis. By contrast, CD8(+)CD161(++)Vα7.2(+) MAIT cells were not protected from the anti‐proliferative and cytotoxic effects of the immunosuppressive MDR1 substrates tacrolimus and mycophenoic acid, although function following MAIT cell‐specific T cell receptor (TCR)‐dependent and ‐independent stimulation was preserved on in‐vitro exposure to these agents. Overall, our data further define MDR1 expression by CD161(++) T and MAIT cells and demonstrate the potential for high MDR1 expression by MAIT cells to confer resistance to cytotoxic MDR1 substrates in vivo . As our understanding of the importance of MAIT cells in human immunity and immunopathology grows, this is an important observation for clinical contexts such as the treatment of malignancy, autoimmunity and post‐transplant immunosuppression. John Wiley and Sons Inc. 2018-09-19 2018-11 /pmc/articles/PMC6194332/ /pubmed/30231297 http://dx.doi.org/10.1111/cei.13165 Text en © 2018 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Fergusson, J.R. Ussher, J.E. Kurioka, A. Klenerman, P. Walker, L.J. High MDR‐1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR‐1 substrates |
title | High MDR‐1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR‐1 substrates |
title_full | High MDR‐1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR‐1 substrates |
title_fullStr | High MDR‐1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR‐1 substrates |
title_full_unstemmed | High MDR‐1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR‐1 substrates |
title_short | High MDR‐1 expression by MAIT cells confers resistance to cytotoxic but not immunosuppressive MDR‐1 substrates |
title_sort | high mdr‐1 expression by mait cells confers resistance to cytotoxic but not immunosuppressive mdr‐1 substrates |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194332/ https://www.ncbi.nlm.nih.gov/pubmed/30231297 http://dx.doi.org/10.1111/cei.13165 |
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