Veillette, A. | bioRxiv Science

bioRxiv2019

SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a new T cell checkpoint

SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a bona fide exhaustion marker. By breeding Pmel-1 mice with SLAMF6 KO mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 KO CD8 T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1xSLAMF6 KO cells, and upon activation, they acquired an effector-memory phenotype. Blocking LAG-3 improved the function of SLAMF6 deficient T cells even further. Finally, adoptive transfer of Pmel-1xSLAMF6 KO T cells into melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. These results support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8 T cells to eradicate tumors.

physiology↗

bioRxiv2019

Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

During thymic development, {gamma}{delta} T cells commit to either an IFN-{gamma}- or an IL-17-producing phenotype through mechanisms that remain unclear. Here, we investigated whether the SLAM/SAP signaling pathway played a role in the functional programming of thymic {gamma}{delta} T cells. Characterization of SLAM family receptor expression revealed that thymic {gamma}{delta} T cell subsets were each marked by distinct co-expression profiles of SLAMF1, SLAMF4, and SLAMF6. In the thymus, immature CD24hi V{gamma}1 and V{gamma}4 {gamma}{delta} T cells were largely contained within a SLAMF1+SLAMF6+ double positive (DP) population, while mature CD24low subsets were either SLAMF1+ or SLAMF6+ single positive (SP) cells. In the periphery, SLAMF1 and SLAMF6 expression on V{gamma}1, V{gamma}4, and V{gamma}6 T cells distinguished IL-17- and IFN-{gamma}-producing subsets, respectively. Disruption of SLAM family receptor signaling through deletion of SAP resulted in impaired thymic {gamma}{delta} T cell maturation at the CD24hiSLAMF1+SLAMF6+ DP stage that was associated with a decreased frequency of CD44+ROR{gamma}t+ {gamma}{delta} T cells. These defects were in turn associated with impaired {gamma}{delta} T cell IL-17 and IFN-{gamma} production in both the thymus as well as in peripheral tissues. The role for SAP was subset-specific, as V{gamma}1, 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 regulates a critical checkpoint in the functional programming of IL-17 and IFN-{gamma}-producing {gamma}{delta} T cell subsets during thymic development.

immunology↗