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Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes

Multidrug resistance-1 (MDR1) acts as a chemotherapeutic drug efflux pump in tumor cells, although its physiological functions remain enigmatic. Using a recently developed MDR1-knockin reporter allele (Abcb1a(AME)), we found that constitutive MDR1 expression among hematopoietic cells was observed in...

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Autores principales: Chen, Mei Lan, Sun, Amy, Cao, Wei, Eliason, Amber, Mendez, Kayla M., Getzler, Adam J., Tsuda, Shanel, Diao, Huitian, Mukori, Clever, Bruno, Nelson E., Kim, Sang Yong, Pipkin, Matthew E., Koralov, Sergei B., Sundrud, Mark S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201929/
https://www.ncbi.nlm.nih.gov/pubmed/32302378
http://dx.doi.org/10.1084/jem.20191388
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author Chen, Mei Lan
Sun, Amy
Cao, Wei
Eliason, Amber
Mendez, Kayla M.
Getzler, Adam J.
Tsuda, Shanel
Diao, Huitian
Mukori, Clever
Bruno, Nelson E.
Kim, Sang Yong
Pipkin, Matthew E.
Koralov, Sergei B.
Sundrud, Mark S.
author_facet Chen, Mei Lan
Sun, Amy
Cao, Wei
Eliason, Amber
Mendez, Kayla M.
Getzler, Adam J.
Tsuda, Shanel
Diao, Huitian
Mukori, Clever
Bruno, Nelson E.
Kim, Sang Yong
Pipkin, Matthew E.
Koralov, Sergei B.
Sundrud, Mark S.
author_sort Chen, Mei Lan
collection PubMed
description Multidrug resistance-1 (MDR1) acts as a chemotherapeutic drug efflux pump in tumor cells, although its physiological functions remain enigmatic. Using a recently developed MDR1-knockin reporter allele (Abcb1a(AME)), we found that constitutive MDR1 expression among hematopoietic cells was observed in cytolytic lymphocytes—including CD8(+) cytotoxic T lymphocytes (CTLs) and natural killer cells—and regulated by Runt-related (Runx) transcription factors. Whereas MDR1 was dispensable for naive CD8(+) T cell development, it was required for both the normal accumulation of effector CTLs following acute viral infection and the protective function of memory CTLs following challenge with an intracellular bacterium. MDR1 acted early after naive CD8(+) T cell activation to suppress oxidative stress, enforce survival, and safeguard mitochondrial function in nascent CTLs. These data highlight an important endogenous function of MDR1 in cell-mediated immune responses and suggest that ongoing efforts to intentionally inhibit MDR1 in cancer patients could be counterproductive.
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spelling pubmed-72019292020-11-04 Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes Chen, Mei Lan Sun, Amy Cao, Wei Eliason, Amber Mendez, Kayla M. Getzler, Adam J. Tsuda, Shanel Diao, Huitian Mukori, Clever Bruno, Nelson E. Kim, Sang Yong Pipkin, Matthew E. Koralov, Sergei B. Sundrud, Mark S. J Exp Med Brief Definitive Report Multidrug resistance-1 (MDR1) acts as a chemotherapeutic drug efflux pump in tumor cells, although its physiological functions remain enigmatic. Using a recently developed MDR1-knockin reporter allele (Abcb1a(AME)), we found that constitutive MDR1 expression among hematopoietic cells was observed in cytolytic lymphocytes—including CD8(+) cytotoxic T lymphocytes (CTLs) and natural killer cells—and regulated by Runt-related (Runx) transcription factors. Whereas MDR1 was dispensable for naive CD8(+) T cell development, it was required for both the normal accumulation of effector CTLs following acute viral infection and the protective function of memory CTLs following challenge with an intracellular bacterium. MDR1 acted early after naive CD8(+) T cell activation to suppress oxidative stress, enforce survival, and safeguard mitochondrial function in nascent CTLs. These data highlight an important endogenous function of MDR1 in cell-mediated immune responses and suggest that ongoing efforts to intentionally inhibit MDR1 in cancer patients could be counterproductive. Rockefeller University Press 2020-04-16 /pmc/articles/PMC7201929/ /pubmed/32302378 http://dx.doi.org/10.1084/jem.20191388 Text en © 2020 Chen et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Brief Definitive Report
Chen, Mei Lan
Sun, Amy
Cao, Wei
Eliason, Amber
Mendez, Kayla M.
Getzler, Adam J.
Tsuda, Shanel
Diao, Huitian
Mukori, Clever
Bruno, Nelson E.
Kim, Sang Yong
Pipkin, Matthew E.
Koralov, Sergei B.
Sundrud, Mark S.
Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes
title Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes
title_full Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes
title_fullStr Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes
title_full_unstemmed Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes
title_short Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes
title_sort physiological expression and function of the mdr1 transporter in cytotoxic t lymphocytes
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201929/
https://www.ncbi.nlm.nih.gov/pubmed/32302378
http://dx.doi.org/10.1084/jem.20191388
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