CD3/SLAMF3-mediated co-stimulation promotes activation of the IL-2/IL-2R/STAT5 pathway and iTreg differentiation in naïve CD4+ T cells - implications for systemic lupus erythematosus (HUM3P.246)

Abstract

Abstract We examined SLAMF3-mediated co-stimulation on IL-2 response of CD4+ T cells from SLE patients. Stimulation of naïve CD4+ T cells with aCD3/aSLAMF3 upregulated surface CD25 (IL-2Ra) and CD122 (IL-2Rb), at higher level compared to aCD3/aCD28 activation. aCD3/aSLAMF3 co-stimulation of control naïve CD4+ T cells led to increased pSTAT5 levels compared to aCD3/aCD28 activation Although naïve CD4+ T cells from SLE patients displayed decreased pSTAT5 levels compared to control donors upon aCD3 or aCD3/aCD28 stimulation, co-stimulation of SLE T cells with aSLAMF3 restored pSTAT5 to normal levels. Total STAT5 levels remained unaltered after T cell activation. Exogenous IL-2 increased proliferation of aCD3/aSLAMF3-activated CD4+ T cells compared to aCD3/aCD28 stimulation. Naïve CD4+ T cells activated with aCD3/aSLAMF3 under iTreg polarizing condition expressed significantly higher levels of FoxP3, CD25 and CTLA-4 compared to aCD3/aCD28 activation. In conclusion, SLAMF3-mediated co-stimulation enhances CD4+ T cell response to IL-2 in SLE patients by acting on the IL-2/IL-2R/STAT5 signaling pathway, increases naïve CD4+ T cell proliferation in response to exogenous IL-2 and can promote iTreg phenotype generation. Of note, SLAMF3-mediated co-stimulation does not increase IL-2 by CD4+ T cells per se. Thus, aSLAMF3-based Ab therapy may emerge as a promising therapeutic agent in SLE by enhancing response to IL-2 and promoting iTreg differentiation.