SLAM/SAP signaling regulates discrete γδ T cell developmental checkpoints and shapes the innate-like γδ TCR repertoire

Abstract

During thymic development, most γδ T cells acquire innate-like characteristics that are critical for their function in tumor surveillance, infectious disease, and tissue repair. The mechanisms, however, that regulate γδ T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like γδ T cell subsets. Here, we utilized a single-cell proteogenomics approach coupled with γδ V(D)J profiling to map the transcriptional landscape, TCR repertoire, and developmental checkpoints of SAP-dependent mouse γδ T cells. We found that SAP mediates its effects on immature, uncommitted thymic γδ T cells and that it simultaneously promotes progression through the γδT17 developmental pathway while also inhibiting the diversion of γδ T cells into the αβ T cell pathway. The redirection of γδ T cell clonotypes into the αβ T cell pathway was associated with a decreased frequency of these mature clonotypes in neonatal thymus, and an altered γδT17 TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent γδT1 Vγ4 T cell subset. Altogether, these data suggest that SLAM/SAP signaling acts during the very early stages of γδ T cell development, where it regulates critical pathways involved in the development of specific γδ T effector subsets, and influences the establishment of a unique innate-like γδ TCR repertoire in both the thymus and the periphery.