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

Abstract

During thymic development, most {gamma}{delta} 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 {gamma}{delta} T cell developmental programming remain unclear. Recently, we demonstrated that the SLAM-SAP signaling pathway regulates the development and function of multiple innate-like {gamma}{delta} T cell subsets. Here, we used a single-cell proteogenomics approach to identify SAP-dependent developmental checkpoints and to define the SAP-dependent {gamma}{delta} TCR repertoire. SAP deficiency resulted in both a significant loss of an immature Gzma+Blk+Etv5+Tox2+{gamma}{delta}T17 precursor population, and a significant increase in Cd4+Cd8+ Rorc+Ptcra+Rag1+ thymic {gamma}{delta} T cells. SAP-dependent diversion of embryonic day 17 thymic {gamma}{delta} T cell clonotypes into the {beta} T cell developmental pathway was associated with a decreased frequency of mature clonotypes in neonatal thymus, and an altered {gamma}{delta} TCR repertoire in the periphery. Finally, we identify TRGV4/TRAV13-4(DV7)-expressing T cells as a novel, SAP-dependent V{gamma}4 {gamma}{delta}T1 subset. Together, the data suggest that SAP-dependent {gamma}{delta}/{beta} T cell lineage commitment regulates {gamma}{delta} T cell developmental programming and shapes the {gamma}{delta} TCR repertoire. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/575073v3_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1d8b5aeorg.highwire.dtl.DTLVardef@7fd02dorg.highwire.dtl.DTLVardef@13c5c76org.highwire.dtl.DTLVardef@1da72b1_HPS_FORMAT_FIGEXP M_FIG C_FIG