Th17 CD4+ cells promote inflammation and autoimmunity. Here we report that Th17 cell frequency is reduced in ob/ob mice that are genetically deficient in the adipokine leptin, and that the administration of leptin to ob/ob mice restored Th17 cell numbers to values comparable to those found in wild type animals. Leptin promoted Th17 responses in normal human CD4+ T cells and in mice, both in vitro and in vivo, by inducing RORγt transcription. Leptin also increased Th17 responses in (NZB × NZW)F1 lupus-prone mice, whereas its neutralization in those autoimmune-prone mice inhibited Th17 responses. Since Th17 cells play an important role in the development and maintenance of inflammation and autoimmunity, these findings envision the possibility to modulate abnormal Th17 responses via leptin manipulation, and reiterate the link between metabolism/nutrition and susceptibility to autoimmunity.

Fasting is beneficial in the prevention and amelioration of the clinical manifestations of autoimmune diseases including systemic lupus erythematosus (SLE). The mechanisms responsible for these effects are not well understood. During fasting, there is a dramatic reduction of the levels of circulating leptin, an adipokine with proinflammatory effects. Leptin also inhibits CD4+CD25+Foxp3+ regulatory T cells (TReg), which are known to contribute significantly to the mechanisms of peripheral immune tolerance. Here we show that fasting-induced hypoleptinemia in (NZB×NZW)F1 lupus-prone mice induced an expansion of functional TReg that was reversed by leptin replacement. The specificity of the findings was indicated by the lack of these effects in leptin-deficient ob/ob mice and in leptin receptor-deficient db/db mice. These observations help to explain the beneficial effects of fasting in autoimmunity and could be exploited for leptin-based immune intervention in SLE.

Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response―a process critical for antibody affinity maturation―is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ABCs and deregulated TFHcell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ABC differentiation, and blocking CD11c+Tbet+ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFHcell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.