Immune cells are increasingly appreciated to play a role in inflammation in adipose and hepatic tissue during obesity and may contribute to the development of non-alcoholic fatty liver disease (NAFLD). Both invariant Natural Killer T (iNKT) cells and B cells are enriched in the liver and adipose tissues of humans and mice, but the degree and nature of their influence in the development of NAFLD remains unclear. iNKT cells interact with B cells in many contexts, including during the chronic inflammation associated with autoimmune disease and infection, so it is likely they interact during obesity. Emerging evidence implicates intrahepatic B cells in the progression of human NAFLD, and proinflammatory B cells increase in the steatotic livers of HFD-fed mice. Our preliminary studies demonstrate an iNKT cell-dependent expansion of inflammatory CD11c+ T-bet+ B cells in the subcutaneous adipose tissue of obese humans and perigonadal adipose tissue of obese mice. We now extend those findings to other iNKT cell-rich fatty depots. Flow cytometry identified increased frequencies of T-bet+ B cells in the livers, but not the omenta or mesenteric adipose tissue, of obese mice. In parallel to the in vivo studies, in vitro co-cultures revealed that iNKT cells are sufficient to mediate expansion of T-bet+ B cells. Ongoing experiments will examine the potential role and mechanism of iNKT cells in mediating hepatic Tbet+ B cell expansion. Characterization of the specific contribution of immune inflammation in the progression NAFLD to NASH will allow for the design of successful therapeutic interventions for this increasingly frequent public health problem. Funding support from NIH K12GM111726 (BTE), NIH TL1 TR002647 (TS), Swedish Research Council (TH), and NIH R01 AI32798-01A1 (EAL).

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Obesity is a burgeoning public health crisis, responsible for increasing chronic systemic inflammation which leads to metabolic disease in humans and mice. Understanding the contribution of immune inflammation to metabolic disease is critical for designing effective therapeutic interventions. Invariant Natural Killer T (iNKT) cells are enriched in the adipose tissue, liver, and omenta of both humans and mice, but their frequency is reduced in adipose during obesity. iNKT cells negatively regulate or positively activate other immune cells, including B cells, depending on the immunologic context. Adipose B regulatory cells protect against inflammation, but they are not the only subset of B cells in adipose tissue. Our preliminary studies find increased frequencies of inflammatory Tbet+ B cells in adipose tissue of obese humans and mice which correlates with weight gain in mice and increasing BMI in humans. We now extend those findings to consider iNKT cell interaction with B cells during obesity in the adipose, liver, and omental tissues. Flow cytometry confirmed iNKT cell-dependent expansion of Tbet+ CD11c+ B cells in adipose tissue of obese mice. Interestingly, similar expansion was not observed in liver or omental tissue from the same obese mice. Instead, the livers and omenta of obese mice demonstrated significant increases in iNKT cell frequency compared with lean mice. In contrast to the adipose tissue, the increase in liver and omental iNKT cells during obesity was missing in mice genetically deficient in Tbet+ B cells. Thus, we find that iNKT cell-dependent expansion of Tbet+ CD11c+ B cells within adipose tissue of obese mice is counter-balanced by a reciprocal Tbet+ B cell-dependent expansion of iNKT cells in liver and omentum.