SLAM-associated protein deficiency in T cells from patients with systemic lupus erythematosus contributes to early signaling abnormalities and reduced IL-2 production (IRM7P.704)

Abstract

Abstract T cells are key players in the pathogenesis of systemic lupus erythematosus (SLE), a chronic autoimmune disease. Following TCR stimulation, SLE T cells display increased levels of tyrosine phosphorylated proteins (pTyr) and augmented calcium (Ca++) responses compared to healthy donors. Impaired IL-2 and excessive IFNγ production also characterize SLE T cells. X-linked lymphoproliferative syndrome (XLP) is an immunodeficiency caused by loss-of-function mutations of the SLAM-associated protein (SAP), a SH2-domain-containing cytoplasmic adaptor molecule. XLP T cells display TCR-mediated early signaling aberrations and a cytokine profile similar to SLE. We determined SAP protein and mRNA levels in SLE T cells and found them significantly decreased. Silencing of SAP in normal T cells resulted in increased pTyr levels and Ca++ flux following aCD3 stimulation. Interestingly, silencing of SAP resulted in decreased IL-2 production. Forced expression of SAP in SLE T cells restored pTyr levels and Ca++ responses to normal levels while the production of IL-2 was corrected to normal levels. In conclusion, SLE T cells display reduced levels of the protein adaptor SAP and that restoration of SAP protein levels corrects the early signaling transduction defects and restores IL-2 production. Approaches to restore SAP levels in SLE T cells may prove of therapeutic value.