CD11c+ Tbet+ B cells constrain obesity- and vaccination-induced germinal center B cells and T helper cells

Obesity is a rapidly growing public health crisis associated simultaneously with increased metabolic disease and humoral immune suppression to vaccination or infection. Inflammatory CD11c+T-bet+ B cells (ABCs) increase in spleen and adipose tissue during obesity and exacerbate metabolic dysfunction via antibodies. We now find that during obesity Tbet+ B cells also expand in the liver but not omentum or mesenteric fat. Obese mice also develop increased splenic CXCR5+ T _FH and hepatic CXCR5-T _PH cells which serve as likely partners for antigen-experienced MHC-II+ ABCs. We also observed that antibodies in obese mice, previously found to contribute to metabolic disease, largely circulate as inflammatory autoantigen-bound immune complexes. Perhaps most striking was our observation that obese mice lacking T-bet in B cells develop increased autoantibody titers and expanded splenic germinal center (GC) B and T helper cells. T-bet+ B cell-deficient mice make a similarly enhanced GC, T _FH , T _PH response to haptenated-protein vaccination with a corresponding increase in antibody affinity, although there is no additive effect of obesity. These results are consistent with GC inhibition by expanded ABCs demonstrated by others to occur during autoimmunity, suggesting a broadly universal mechanism which may also explain reduced humoral immunity and poor clinical outcomes following infection in patients with obesity and other forms of chronic inflammation.