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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...

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Detalles Bibliográficos
Autores principales: 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.
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
Descripción
Sumario: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.