Tbet+CD11c+ B cells depend on CD36 for expansion and effector function during obesity 2258257

Abstract

Abstract Introduction CD21- CD23- CD11c+ Tbet+ B cells expand in primary immune and peripheral tissues during chronic conditions such as aging, autoimmune diseases, and obesity. These antigen experienced B cells largely produce IgG2a/c autoantibodies which exacerbate autoimmunity and metabolic dysfunction, positioning them as a promising therapeutic target. Typically, Tbet+ CD11c+ B cells expand in vitro and in vivo in response to a combination of TLR agonists, cytokines, and CD4+ T cell help, but the nature and coordination of signals involved in their expansion and effector function remain poorly understood. We have discovered that Tbet+ CD11c+ B cells express high levels of class B scavenger receptor and fatty acid translocase CD36. CD36 is capable of innate signaling, antigen uptake and metabolic reprogramming, all of which could be contributing to B cell activity. Methods This project combines unique mouse strains engineered to lack CD36 selectively in B cells with high fat diet-induced obesity or bm12 autoimmune mouse models. We are determining the relative contribution of CD36 to Tbet+CD11c+ B cell expansion and effector function. Results Mice lacking CD36 in B cells fail to expand inflammatory CD11c+Tbet+ B cells or accompanying splenic TFH/TPH cells to the same level as BWT controls during high fat diet-induced obesity. HFD-fed obese mice lacking CD36 on B cells also develop significantly lower levels of anti-oxLDL and anti-dsDNA IgG2c autoantibodies than WT control mice. This effect may extend to additional effector functions including antibodies and cytokine production. We will also determine if Tbet+ B cell dependence on CD36 extends to cGVHD lupus mice. Conclusion Elaborating a better understanding of signals employed by CD36 during expansion and function of CD11c+Tbet+ B cells will allow targeted clinical interventions and could improve immune responses to vaccination or infection for patients with obesity, autoimmunity, or related chronic inflammatory conditions. Funding Source The Flow Cytometry Shared Resource at UT Health San Antonio is supported by the National Cancer Institute (P30CA054174) through the Mays Cancer Center, the Cancer Prevention and Research Institute of Texas (CPRIT) (RP210126), the National Institutes of Health (S10OD030432), and the Office of the Vice President for Research at UT Health San Antonio. This work was also supported by critical funding from the National Institutes of Health: R01 AI32789-01A1 (EAL), R21 AI183125-01A1 (EAL), K12 GM111726 (BTE), T32 DE014318 (EC). Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)