No abstract

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).

Obesity is a complex condition that affects a large part of the global population, making it a major risk factor for premature mortality and medical complications. Obesity profoundly engages the immune system, impacting cancer immunity, infections, and autoimmunity. Additionally, obesity is associated with a low-grade chronic inflammation which exacerbates metabolic dysfunction. B cells play a significant role in obesity-associated inflammation and metabolic dysfunction, but their effect is subset-dependent and can be either protective or pathogenic. Therefore, understanding how different B cell populations contribute to these phenotypes represent a crucial goal. Our lab has identified a subset of B lymphocytes which is expanded in the adipose tissue of humans and mice during obesity. These B cells co-express the transcription factor T-bet and the integrin CD11c, and they produce IgG2c antibodies. In vivo studies with mice fed a high fat diet revealed that these Tbet+ B cells promote inflammation through the production of proinflammatory antibodies. Additionally, these B cells express high levels of the scavenger receptor CD36, a lipid-transport molecule associated with inflammation and atherosclerosis. As a potential consequence of the CD36 expression, the Tbet+ B cells maintain a higher intracellular lipid content and are capable of increased uptake of oxidized LDL compared to conventional B cells, suggesting a unique lipid metabolism. Because of their unique nature, T-bet+ B cells represent a potential link between obesity, inflammation, and autoimmunity. Identifying the mechanisms regulating their function will provide new potential targets to reduce inflammation and immunological dysfunction in obese patients. Supported by R01 AI132798

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.

Obesity is a public health crisis affecting a large and ever-growing portion of the global population. Obesity is associated with an increased risk of death and comorbidities, resulting in lower quality of life for obese patients and increased economic costs on healthcare systems. Obesity is linked with a low-grade and chronic inflammation in the adipose tissue, which further exacerbates metabolic dysfunctions. Understanding the mechanisms and immune cell types promoting this inflammation would allow for the development of new therapies to restore immune regulation in obese patients. Our lab has identified a subset of B lymphocytes which is expanded in the adipose tissue of humans and mice during obesity. This subset is characterized by the co-expression of T-bet and CD11c, production of IgG2c, and its expansion is dependent on the presence of iNKT cells. In vivo studies with mice fed a high fat diet reveal that these Tbet+ B cells promote inflammation. Serum transfer experiments and flow cytometry analysis revealed that this effect is mediated through the production of CXCL10 and antibodies. The absence of T-bet+ B cells does not appear to affect adipose CD4+ T cells or NK cells, but it reduces macrophage polarization towards a more proinflammatory phenotype. Transgenic mice engineered to lack T-bet+ B cells not only have reduced adipose tissue inflammation, but present improved metabolic function as well, gaining less weight on a high-fat diet than littermate controls and presenting improved glucose tolerance. Based on these results, T-bet+ B cells represent an interesting potential target to reduce inflammation in obese patients and improve their metabolic functions.