The Sle2c1 murine susceptibility locus controls T cell homeostasis through defective IL-2 production (49.15)

Abstract

Abstract The function of the Sle2 mouse lupus susceptibility locus and its derived Sle2c1sublocus have been previously shown to be associated with a lower threshold of activation of the BCR leading to an accumulation of B1a cells in NZM2410 model. To explore whether these loci had any effects on other immune components, we introduced lpr as an amplifier into B6.Sle2 and its subcongenic strains, and analyzed systemically their cellular and functional phenotypes. Consequently it was found that the co-expression of Sle2 and lpr on a C57BL/6 background significantly increased lymphadenopathy primarily targeting T cells, as well as induced renal pathology which included heavy lymphoid infiltrates. Comparison of the 3 Sle2 subloci mapped the synergistic interaction with lpr to Sle2c. Further examination of both Fas-deficient and Fas-intact mice showed that Sle2c1 resulted in increased T cell proliferation, a reduced IL-2 production, and a reduced Foxp3+ regulatory T cell compartment in spleen and lymph nodes, phenotypes which are characteristic of lupus in human patients and mouse models. Our results demonstrate that the Sle2c1 locus contains a candidate gene which, in addition to regulate BRC activation threshold, also affects T cells homeostasis through altering IL-2 production and Treg cell balance.