Dissecting the role of CD36 on Tbet+ B cells during obesity and autoimmunity

About This Grant

CD21-CD23- CD11c+ Tbet+ Age Associated B Cells or ABCs, expand in primary immune and peripheral tissues during chronic conditions such as aging, autoimmune diseases, atherosclerosis, and obesity. These ABCs largely produce IgG2a/c autoantibodies which exacerbate autoimmunity and metabolic dysfunction, positioning them as a promising therapeutic target for a broad array of inflammatory and infectious diseases. Furthermore, ABCs have recently been found to inhibit germinal center responses to conventional antigens such as those in most effective vaccines, which could explain the poor vaccine outcomes in elderly, autoimmune, and obese patients. As such, this suggests that blocking ABCs may improve vaccine responses across a broad array of platforms. ABCs expand in vitro and in vivo in response to a combination of TLR agonists, cytokines like IFNg and IL-21 as well as CD4+ T cell help, but the nature and coordination of signals which mediate ABC expansion and effector function remain inadequately understood. We recently discovered that ABC cells express unexpectedly high levels of class B scavenger receptor and fatty acid translocase CD36. Even more interesting, expansion of ABCs during obesity or in response to TLR7 inflammatory stimulation requires CD36, suggesting a role for CD36 in stimulation or maintenance of this unique B cell subset during chronic inflammation of obesity and autoimmunity. CD36 is capable of a myriad of different roles, including innate signaling, efficient uptake of antigen and metabolic reprograming, any one of which could be contributing to ABC activity. For example, CD36 mediated fatty acid uptake and subsequent PPAR-beta signaling support mitochondrial oxidative phosphorylation over glycolysis. In addition to mediating lipid uptake for metabolic regulation, CD36 also binds long chain fatty acids including oxidized phospholipids and pattern associated molecular patterns (DAMPS/PAMPS) such as apoptotic cells and amyloid proteins which could be presented by MHC II to engage helper T cells. CD36 engagement also triggers intracellular signaling cascades leading to innate activation and secretion of inflammatory cytokines. This project aims to combine unique mouse strains engineered to lack CD36 selectively in B cells with inflammatory in vivo mouse models to determine the relative contribution of CD36 to mediating antigen uptake and presentation, innate immune activation, and metabolic engagement by ABC cells during obesity or autoimmune disease. Elaborating a better understanding of signals employed by CD36 during activation of ABCs will allow targeted clinical interventions to slow their inflammatory contribution to disease and also improve immune responses to vaccination or infection for patients with obesity, autoimmune disease, or related chronic inflammatory conditions.