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

ABSTRACT: During thymic development, mouse ?? T cells commit to either an IFN-?- 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 ?? T cells. Characterization of SLAM family receptor expression revealed that thymic ?? T cell subsets were each marked by distinct coexpression profiles of SLAMF1, SLAMF4, and SLAMF6. In the thymus, V?1 and V?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-?-producing ?? T cells, respectively. Disruption of SLAM family receptor signaling through deletion of SAP resulted in impaired thymic V?1 and V?4 T cell maturation at the CD24⁺CD73^-SLAMF1⁺SLAMF6⁺ double positive stage that was associated with a decreased frequency of CD44⁺ROR?t⁺ ?? T cells. Impaired development was in turn associated with decreased ?? T cell IL-17 and IFN-? production in the thymus as well as in peripheral tissues. The role for SAP was subset-specific, as V?1V?6.3, V?4, V?5, but not V?6 subsets were SAP-dependent. Together, these data suggest that the SLAM/SAP signaling pathway plays a larger role in ?? T cell development than previously appreciated and represents a critical checkpoint in the functional programming of both IL-17- and IFN-?-producing ?? T cell subsets.

SUBMITTER: Dienz O

PROVIDER: S-EPMC7065973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A major limitation of most animal models of autoimmune diseases is that they do not reproduce the chronic or relapsing-remitting pattern characteristic of many human autoimmune diseases. This problem has been overcome in our rat models of experimentally induced monophasic or relapsing-remitting autoimmune uveitis (EAU), which depend on the inducing antigen peptides from retinal S-Antigen (monophasic EAU) or interphotoreceptor retinoid-binding protein (relapsing EAU). These models enable us to compare autoreactive and regulatory T cell populations. Intraocular, but not peripheral T cells differ in their cytokine profiles (IFN-?, IL-17 and IL-10) at distinct time points during monophasic or relapsing EAU. Only intraocular T cells concomitantly produced IFN-?, IL-17 and/or IL-10. Monophasic EAU presented rising numbers of cells expressing IFN-? and IL-17 (Th1/Th17) and cells expressing IL-10 or Foxp3. During relapsing uveitis an increase of intraocular IFN-?+ cells and a concomitant decrease of IL-17+ cells was detected, while IL-10+ populations remained stable. Foxp3+ cells and cells expressing IL-10, even in combination with IFN-? or IL-17, increased during the resolution of monophasic EAU, suggesting a regulatory role for these T cells. In general, cells producing multiple cytokines increased in monophasic and decreased in relapsing EAU. The distinct appearance of certain intraocular populations with characteristics of regulatory cells points to a differential influence of the ocular environment on T cells that induce acute and monophasic or relapsing disease. Here we provide evidence that different autoantigens can elicit distinct and differently regulated immune responses. IFN-?, but not IL-17 seems to be the key player in relapsing-remitting uveitis, as shown by increased, synchronized relapses after intraocular application of IFN-?. We demonstrated dynamic changes of the cytokine pattern during monophasic and relapsing-remitting disease with strongly increasing IL-10 expression in intraocular T cells during monophasic uveitis.

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

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