[PDF][PDF] SAP regulates TH2 differentiation and PKC-θ-mediated activation of NF-κB1

JL Cannons, JY Li, B Hill, LA Mijares, D Dombroski… - Immunity, 2004 - cell.com
JL Cannons, JY Li, B Hill, LA Mijares, D Dombroski, KE Nichols, A Antonellis, GA Koretzky
Immunity, 2004cell.com
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-γ and decreased TH 2 cytokine production. We demonstrate
that the defect in IL-4 secretion in SAP-deficient T cells is independent of increased IFN-γ
production. SAP-deficient cells respond normally to polarizing cytokines, yet show impaired …
Abstract
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-γ and decreased TH2 cytokine production. We demonstrate that the defect in IL-4 secretion in SAP-deficient T cells is independent of increased IFN-γ 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-θ recruitment, Bcl-10 phosphorylation, IκB-α degradation, and nuclear NF-κB1/p50 levels. Similar defects were observed in Fyn-deficient cells. SLAM engagement amplified PKC-θ recruitment in wt but not SAP- or Fyn-deficient cells, arguing that a SAP/Fyn-mediated pathway enhances PKC-θ/NF-κB1 activation and suggesting a role for this pathway in TH2 regulation.
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