Background/Purpose: T cell activation is initiated by engagement of the T cell receptor (TCR) complex and requires co-receptor signaling. SLAMF6 is a major T cell co-receptor and aberrant signaling downstream this receptor has have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Moreover, genome association studies in spontaneous murine lupus models of SLE associated SLAMF6 polymorphisms with loss of tolerance, autoantibody production, and susceptibility to SLE.

Accordingly, uncovering the mechanism of SLAMF6 signaling in autoimmune T cells could improve our understanding of the biology of SLE and could have translational therapeutic implications.

Methods: Activation of Jurkat T cells (ATCC) with 1) immobilized anti-CD3 and anti-SLAMF6 allowed for SLAMF6 clustering to the immunological synapse (IS) or 2) immobilized anti-CD3 and soluble anti-SLAMF6 resulted in exclusion of SLAMF6 from the IS. ELISA was used to measure cytokine secretion and CFSE assay to assess T cell proliferation. Co-immuno precipitation of SLAMF6 was performed using a SLAMF6 knock-out cell line that was transduced to express V5-tagged SLAMF6, results were analyzed using protein electrophoresis with immunoblotting and mass spectrometry.

SLAMF6 expression was evaluated in lymphocytes isolated from the peripheral blood of SLE patients with well characterized clinical phenotypes.

Results: Previously we discovered that SLAMF6 clustering is a requirement for its co-stimulatory functions. In the current work, we show that SLAMF6 recruitment to the immunological synapse (IS) is needed to support T cell proliferation and survival. Using confocal microscopy, we also show a direct correlation between SLAMF6 localization within the different compartments of the IS and the ability of this receptor to enhance secretion of multiple cytokines. Mechanistically, and through co-immunoprecipitation experiments, we reveal that SLAMF6 recruits several members of the Src family of kinases to IS, leading to enhance proximal phosphorylation of the TCR complex. Finally, taking advantage of Tfh cell isolated from patients with active SLE, we show that specific pharmacological interventions that prevent SLAMF6 clustering inhibit TCR signaling and multiple effector functions.

Conclusion: This transitional study advances the understanding of how SLAMF6 contribute to SLE pathogenesis, linking known SLE susceptible genes to specific signaling pathway in autoimmune T cells. Means to manipulate SLAMF6 signaling are promising approaches for novel SLE therapeutics.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/slamf6-compartmentalization-regulates-autoimmune-t-cell-responses/