Cargando…
STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function
Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunode...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451129/ https://www.ncbi.nlm.nih.gov/pubmed/25941256 http://dx.doi.org/10.1084/jem.20141992 |
_version_ | 1782374099803176960 |
---|---|
author | Wilson, Robert P. Ives, Megan L. Rao, Geetha Lau, Anthony Payne, Kathryn Kobayashi, Masao Arkwright, Peter D. Peake, Jane Wong, Melanie Adelstein, Stephen Smart, Joanne M. French, Martyn A. Fulcher, David A. Picard, Capucine Bustamante, Jacinta Boisson-Dupuis, Stephanie Gray, Paul Stepensky, Polina Warnatz, Klaus Freeman, Alexandra F. Rossjohn, Jamie McCluskey, James Holland, Steven M. Casanova, Jean-Laurent Uzel, Gulbu Ma, Cindy S. Tangye, Stuart G. Deenick, Elissa K. |
author_facet | Wilson, Robert P. Ives, Megan L. Rao, Geetha Lau, Anthony Payne, Kathryn Kobayashi, Masao Arkwright, Peter D. Peake, Jane Wong, Melanie Adelstein, Stephen Smart, Joanne M. French, Martyn A. Fulcher, David A. Picard, Capucine Bustamante, Jacinta Boisson-Dupuis, Stephanie Gray, Paul Stepensky, Polina Warnatz, Klaus Freeman, Alexandra F. Rossjohn, Jamie McCluskey, James Holland, Steven M. Casanova, Jean-Laurent Uzel, Gulbu Ma, Cindy S. Tangye, Stuart G. Deenick, Elissa K. |
author_sort | Wilson, Robert P. |
collection | PubMed |
description | Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers. |
format | Online Article Text |
id | pubmed-4451129 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-44511292015-12-01 STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function Wilson, Robert P. Ives, Megan L. Rao, Geetha Lau, Anthony Payne, Kathryn Kobayashi, Masao Arkwright, Peter D. Peake, Jane Wong, Melanie Adelstein, Stephen Smart, Joanne M. French, Martyn A. Fulcher, David A. Picard, Capucine Bustamante, Jacinta Boisson-Dupuis, Stephanie Gray, Paul Stepensky, Polina Warnatz, Klaus Freeman, Alexandra F. Rossjohn, Jamie McCluskey, James Holland, Steven M. Casanova, Jean-Laurent Uzel, Gulbu Ma, Cindy S. Tangye, Stuart G. Deenick, Elissa K. J Exp Med Brief Definitive Report Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers. The Rockefeller University Press 2015-06-01 /pmc/articles/PMC4451129/ /pubmed/25941256 http://dx.doi.org/10.1084/jem.20141992 Text en © 2015 Wilson et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Brief Definitive Report Wilson, Robert P. Ives, Megan L. Rao, Geetha Lau, Anthony Payne, Kathryn Kobayashi, Masao Arkwright, Peter D. Peake, Jane Wong, Melanie Adelstein, Stephen Smart, Joanne M. French, Martyn A. Fulcher, David A. Picard, Capucine Bustamante, Jacinta Boisson-Dupuis, Stephanie Gray, Paul Stepensky, Polina Warnatz, Klaus Freeman, Alexandra F. Rossjohn, Jamie McCluskey, James Holland, Steven M. Casanova, Jean-Laurent Uzel, Gulbu Ma, Cindy S. Tangye, Stuart G. Deenick, Elissa K. STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function |
title | STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function |
title_full | STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function |
title_fullStr | STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function |
title_full_unstemmed | STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function |
title_short | STAT3 is a critical cell-intrinsic regulator of human unconventional T cell numbers and function |
title_sort | stat3 is a critical cell-intrinsic regulator of human unconventional t cell numbers and function |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451129/ https://www.ncbi.nlm.nih.gov/pubmed/25941256 http://dx.doi.org/10.1084/jem.20141992 |
work_keys_str_mv | AT wilsonrobertp stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT ivesmeganl stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT raogeetha stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT lauanthony stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT paynekathryn stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT kobayashimasao stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT arkwrightpeterd stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT peakejane stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT wongmelanie stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT adelsteinstephen stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT smartjoannem stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT frenchmartyna stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT fulcherdavida stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT picardcapucine stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT bustamantejacinta stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT boissondupuisstephanie stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT graypaul stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT stepenskypolina stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT warnatzklaus stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT freemanalexandraf stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT rossjohnjamie stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT mccluskeyjames stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT hollandstevenm stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT casanovajeanlaurent stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT uzelgulbu stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT macindys stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT tangyestuartg stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction AT deenickelissak stat3isacriticalcellintrinsicregulatorofhumanunconventionaltcellnumbersandfunction |