Recruitment of calcineurin to the TCR positively regulates T cell activation.
Nat Immunol
; 18(2): 196-204, 2017 02.
Article
em En
| MEDLINE
| ID: mdl-27941787
ABSTRACT
Calcineurin is a phosphatase whose primary targets in T cells are NFAT transcription factors, and inhibition of calcineurin activity by treatment with cyclosporin A (CsA) or FK506 is a cornerstone of immunosuppressive therapies. Here we found that calcineurin was recruited to the T cell antigen receptor (TCR) signaling complex, where it reversed inhibitory phosphorylation of the tyrosine kinase Lck on Ser59 (LckS59). Loss of calcineurin activity impaired phosphorylation of Tyr493 of the tyrosine kinase ZAP-70 (ZAP-70Y493), as well as some downstream pathways in a manner consistent with signaling in cells expressing LckS59A (Lck that cannot be phosphorylated) or LckS59E (a phosphomimetic mutant). Notably, CsA inhibited integrin-LFA-1-dependent and NFAT-independent adhesion of T cells to the intercellular adhesion molecule ICAM-1, with little effect on cells expressing mutant Lck. These results provide new understanding of how widely used immunosuppressive drugs interfere with essential processes in the immune response.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores de Antígenos de Linfócitos T
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Linfócitos T
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Calcineurina
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Proteína Tirosina Quinase p56(lck) Linfócito-Específica
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Proteína-Tirosina Quinase ZAP-70
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article