Influence of SLAM/SAP signaling on γδ T cell TCR signal strength during thymic development

Abstract

Abstract Innate-like T cells are unusual T cells that are enriched in mucosal tissues, where they constitute a prominent source of pro-inflammatory cytokines like IL-17 and IFN-γ. During thymic development, mouse γδ T cells commit to either γδT1, γδT2, or γδT17 phenotypes through mechanisms that remain unclear. Recent observations from our laboratory have suggested a role for the SLAM/SAP signaling pathway in γδ T cell thymic developmental programming. Here, we investigated the influence of the SLAM/SAP signaling pathway on γδ TCR signal strength during thymic development. Using Nur77 GFPexpression as a readout of TCR signal strength, we observed significantly greater Nur77 GFPexpression in B6.Nur77 GFP.SAP −/−thymic γδ T cells compared their B6.Nur77 GFPcounterparts, suggesting that SAP inhibited TCR signal strength. Consistent with these findings, we observed significantly greater Erk phosphorylation in CD3-stimulated B6.SAP −/−thymic γδ T cells. In vitrostimulation of thymic γδ T cells with anti-TCRδ and anti-SLAM family receptors revealed that SLAMF6 co-stimulation resulted in decreased Erk phosphorylation, but increased Nur77 GFPexpression. Surprisingly, the effects of SLAMF6 co-stimulation on γδ TCR signaling were SAP-independent. Together, these data suggest an inhibitory role for SAP in γδ TCR signaling during thymic developmental programming.