Critical Role for SLAM/SAP Signaling in the Thymic Developmental Programming of IL-17-and IFN-γ-Producing γδ T Cells

During thymic development, mouse gamma delta T cells commit to either an IFN-gamma -or an IL-17-producing phenotype through mechanisms that remain unclear. In this study, we investigated the extent to which the SLAM/SAP signaling pathway regulates the functional programming of gamma delta T cells. Characterization of SLAM family receptor expression revealed that thymic gamma delta T cell subsets were each marked by distinct coexpression profiles of SLAMF1, SLAMF4, and SLAMF6. In the thymus, V gamma 1 and V gamma 4 T cells that exhibited an SLAMF1(+) SLAMF6(+) double positive phenotype were largely contained within immature CD24(+)CD73(-) and CD24(+)CD73(-) subsets, whereas SLAMF1 single positive, SLAMF6 single positive, or SLAMF1SLAMF6 double negative cells were found within mature CD24(-) CD73(+) and CD24(-) CD73(-) subsets. In the periphery, SLAMF1 and SLAMF6 expression distinguished IL-17- and IFN-gamma-producing gamma delta T cells, respectively. Disruption of SLAM family receptor signaling through deletion of SAP resulted in impaired thymic V gamma 1 and V gamma 4 T cell maturation at the CD24(+) CD73(-) SLAMF1(+) SLAMF6(+) double positive stage that was associated with a decreased frequency of CD44(+)ROR gamma t(+) gamma delta T cells. Impaired development was in turn associated with decreased gamma delta T cell IL-17 and IFN-gamma production in the thymus as well as in peripheral tissues. The role for SAP was subset-specific, as V gamma 1V delta 6.3, V gamma 4, V gamma 5, but not V gamma 6 subsets were SAP-dependent. Together, these data suggest that the SLAM/SAP signaling pathway plays a larger role in gamma delta T cell development than previously appreciated and represents a critical checkpoint in the functional programming of both IL-17- and IFN-gamma-producing gamma delta T cell subsets.