Gr1+ Cells Suppress T-Dependent Antibody Responses in (NZB x NZW)F1 Male Mice through Inhibition of T Follicular Helper Cells and Germinal Center Formation

Systemic lupus erythematosus is an autoimmune disease characterized by elevated production of autoreactive Abs. The disease has a much higher prevalence in women than in men. Although testosterone has been shown to be protective in the disease, and estrogens exacerbating, the discrepancy in prevalence between men and women is still not well understood and the mechanism behind it is unknown. We have recently described that male (New Zealand black [NZB] x New Zealand white [NZW])F1 mice have higher levels of Gr1(+)CD11b(+) cells, and that these cells suppress autoantibody production in vivo. In this article, we extend our findings to show that similarly to humans, female lupus-prone (NZB x NZW)F1 mice also respond with stronger Ab responses to thymusdependent Ag immunization than male littermates. Furthermore, the presence or absence of Gr1-expressing cells not only control Ag-specific Ab responses in male, but not female, (NZB x NZW)F1 mice, but also significantly alter the activation and differentiation of CD4(+) T cells in vitro and in vivo. In particular, we found that Gr1(+) cells from male (NZB x NZW)F1 mice suppress the differentiation and effector function of CXCR5(+) PD-1(+) T follicular helper cells, thereby controlling germinal center formation and plasma cell differentiation. This new finding strongly supports efforts to develop new drugs that target myeloid cell subsets in a number of T and B cell-mediated diseases with a female predominance.