IL-21 Receptor Is Required for the Systemic Accumulation of Activated B and T Lymphocytes in MRL/MpJ-Fas/J Mice

MRL/MpJ-Fas lpr/lpr /J (MRL lpr) mice develop lupus-like disease manifestations in an IL-21–dependent manner. IL-21 is a pleio-tropic cytokine that can influence the activation, differentiation, and expansion of B and T cell effector subsets. Notably, auto-reactive CD4 + T and B cells spontaneously accumulate in MRL lpr mice and mediate disease pathogenesis. We sought to identify the particular lymphocyte effector subsets regulated by IL-21 in the context of systemic autoimmunity and, thus, generated MRL lpr mice deficient in IL-21R (MRL lpr .IL-21R 2/2). Lymphadenopathy and splenomegaly, which are characteristic traits of the MRL lpr model were significantly reduced in the absence of IL-21R, suggesting that immune activation was likewise decreased. Indeed, spontaneous germinal center formation and plasma cell accumulation were absent in IL-21R–deficient MRL lpr mice. Correspondingly , we observed a significant reduction in autoantibody titers. Activated CD4 + CD44 + CD62L lo T cells also failed to accumulate, and CD4 + Th cell differentiation was impaired, as evidenced by a significant reduction in CD4 + T cells that produced the pronephritogenic cytokine IFN-g. T extrafollicular helper cells are a recently described subset of activated CD4 + T cells that function as the primary inducers of autoantibody production in MRL lpr mice. Importantly, we demonstrated that T extrafollicular helper cells are dependent on IL-21R for their generation. Together, our data highlighted the novel observation that IL-21 is a critical regulator of multiple pathogenic B and T cell effector subsets in MRL lpr mice. M RL/MpJ-Fas lpr/lpr /J (MRL lpr) mice spontaneously develop systemic autoimmunity that is characterized by generalized activation of B and T cells and patho-logic features resembling those observed in patients with systemic lupus erythematosus (SLE). Hallmark features of disease include the development of glomerulonephritis and cutaneous lesions and production of somatically mutated autoantibodies that recognize nuclear components (1, 2). Multiple lymphocyte effector populations contribute to disease pathogenesis in MRL lpr mice. Both B cells and CD4 + T cells are critical for the development of renal pathology and autoantibody production (3–7). B cells promote the development of disease features via both Ab-dependent and-independent mechanisms and are required for the accumulation of activated memory CD4 + and CD8 + T cells (7, 8). The predominant source of somatically mutated autoantibodies in MRL lpr mice derives from extrafollicular foci that require CD4 + T extra-follicular helper (T hef) cells for their formation (9, 10). CD4 + T hef cells …