Dissecting the mechanism of altered immune responses during obesity

Obesity is a critical global epidemic, leading cause of preventable death, and source of skyrocketing health care costs. According to the CDC, 42% of US adults are now obese, costing the US more than $173 billion/ year. Alterations in immune populations such as macrophages and T cells accompany inflammation, metabolic disease, and poor infection outcomes in obese patients, but there is growing appreciation for important B cell contributions to inflammation and metabolic disease as well. The recent viral pandemic has highlighted the negative immune consequences of obesity, with obese patients showing suboptimal vaccine responses, increased disease pathology, and worse clinical outcomes than lean patients. As part of our efforts to dissect the immune changes during obesity, we recently documented an increase in an inflammatory B cell subset, Tbet+ CD11c+ B cells, in the spleen and adipose tissue of obese humans and mice. These Tbet+ B cells are known to produce IgG2c, expand during infection, autoimmune disease, and aging, and produce protective antibodies during acute infection. On the other hand, Tbet+ B cells with autoimmune reactivity expand during chronic autoimmune diseases and aging. Our preliminary data suggests that 1) obesity induces expansion of a class-switched, extrafollicular, likely low affinity, CD11c+ Tbet+ B cell population in secondary lymphoid organs, 2) but vaccination during obesity does not expand higher affinity GC dependent B cells typically observed during acute infection. Our most compelling data shows that 3) the poor clinical outcomes exhibited by obese animals can be restored by removing Tbet+ B cells. We hypothesize that extrafollicular expansion of Tbet+ B cells during obesity skews humoral immune responses towards lower affinity, shorter lasting IgG, rendering the animal less capable of mounting protective responses against vaccines and infectious virus. Successful completion of this project will provide insight into Tbet+ B cells as a potential therapeutic target for increasing vaccine-driven and protective humoral immune responses in obese patients and may be applicable to immunologically related conditions such as aging and autoimmunity, expanding the therapeutic effect to other clinically vulnerable populations.