SAP Regulates TH2 Differentiation and PKC-θ-Mediated Activation of NF-κB1

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-gamma and decreased T(H)2 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 Ca(2+) mobilization and ERK activation in SAP-deficient cells, but decreased PKC-theta recruitment, Bcl-10 phosphorylation, IkappaB-alpha degradation, and nuclear NF-kappaB1/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-kappaB1 activation and suggesting a role for this pathway in T(H)2 regulation.

Bcl10 Controls TCR- and FcγR-Induced Actin Polymerization

“…Similar modifications resulting in substantial m.w. shifts have also been observed by others (16,18,31,32).…”

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

“…SAP seems to be important for the modulation of TCR signals, leading to the initiation of apoptotic pathways. Cannon's study showed that SAP is recruited to the immune synapse upon TCR stimulation in WT CD4 + T cells, suggesting that SLAM family receptors can fine-tune the TCR signals [16]. Thus, SAP deficiency causes reduced apoptosis in CD8 + T cells, instead of switching off the entire apoptotic pathway.…”

“…It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10]. SAP is expressed in activated T, NK and NKT cells, as well as in germinal center B cells [11,12], and is indispensable for normal NKT cell development, generation of a proper Th2 response and Ig class switching in humans and mice [13][14][15][16][17][18]. In XLP patients, both EBV-infected B cells and EBVspecific CTL hyper-proliferate, although the underlying mechanism is still controversial.…”

Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells

“…GATA-3 is up-regulated in response to IL-4/STAT-6 and TCRinduced signals (4,24). It seemed feasible that a block in GATA-3 expression could underlie the failure of CD4 T cells to commit to the Th2 lineage.…”