SAP Regulates TH2 Differentiation and PKC-[theta]-Mediated Activation of NF-[kappa]B1.
Cannons, Jennifer L. 1; Yu, Li J. 1; Hill, Brenna 1,3; Mijares, Lilia A. 1; Dombroski, Derek 1; Nichols, Kim E. 4; Antonellis, Anthony 1; Koretzky, Gary A. 4,5; Gardner, Kevin 2; Schwartzberg, Pamela L. *,1
[Article] Immunity. 21(5):693-706, November 2004.

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XLP is caused by mutations affecting SAP, an adaptor that recruits Fyn to SLAM family receptors. SAP-deficient mice recapitulate features of XLP, including increased T cell activation and decreased humoral responses post-infection. SAP-deficient T cells also show increased TCR-induced IFN-[gamma] and decreased TH2 cytokine production. We demonstrate that the defect in IL-4 secretion in SAP-deficient T cells is independent of increased IFN-[gamma] production. SAP-deficient cells respond normally to polarizing cytokines, yet show impaired TCR-mediated induction of GATA-3 and IL-4. Examination of TCR signaling revealed normal Ca2 mobilization and ERK activation in SAP-deficient cells, but decreased PKC-[theta] recruitment, Bcl-10 phosphorylation, I[kappa]B-[alpha] degradation, and nuclear NF-[kappa]B1/p50 levels. Similar defects were observed in Fyn-deficient cells. SLAM engagement amplified PKC-[theta] recruitment in wt but not SAP- or Fyn-deficient cells, arguing that a SAP/Fyn-mediated pathway enhances PKC-[theta]/NF-[kappa]B1 activation and suggesting a role for this pathway in TH2 regulation.

(C) 2004Elsevier, Inc.