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Antigen‐induced translocation of SLAT to immunological synapse is required for NFAT activation and Th1/Th2 immune responses
Author(s) -
Becart Stephane,
Charvet Celine,
Caigo Balancio Ann J.,
Altman Am
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.662.1
Subject(s) - nfat , immunological synapse , t cell receptor , microbiology and biotechnology , cd28 , guanine nucleotide exchange factor , t cell , tyrosine phosphorylation , gtpase , phosphorylation , biology , signal transduction , immune system , immunology , transcription factor , biochemistry , gene
SLAT is a novel guanine nucleotide exchange factor for Rho GTPases, which is highly expressed in T cells, but whose physiological function is unclear. SLAT −/− peripheral CD4 + T cells demonstrated impaired TCR/CD28‐induced proliferation and IL‐2 production, which was rescued by the addition of exogenous IL‐2. Importantly, SLAT −/− mice were grossly impaired in their ability to mount Th2 and Th1‐mediated lung inflammatory responses. This defect in mounting Th1/Th2 responses was traced to a severe reduction of Ca 2+ mobilization from ER stores, which consequently led to defective TCR/CD28‐induced NFATc1/2 nuclear translocation. Furthermore, TCR engagement induced SLAT translocation to the immunological synapse (IS) via the Lck‐mediated phosphorylation of two tyrosine residues located in its ITAM‐like sequence. Moreover, this antigen‐induced subcellular relocalization of SLAT was coupled to, and necessary for, specific activation of the NFAT pathway. In addition, once translocated to the IS by a proper targeting signal, the Dbl‐homology (DH) domain of SLAT was sufficient to trigger TCR‐mediated NFAT activation and Th1/Th2 differentiation, most likely via its GEF activity. Therefore, tyrosine phosphorylation‐mediated relocalization of SLAT to the site of antigen recognition is required to exert its pivotal role in NFAT‐dependent CD4 + T cell differentiation.