Obesity is a critical global epidemic, a leading cause of preventable death, and a source of skyrocketing health
care costs. Currently more than two thirds of US adults are overweight and at least one third are considered
obese. It is increasingly appreciated that obesity is linked to chronic, low-grade inflammation in visceral adipose
tissue and an associated spectrum of metabolic abnormalities including insulin resistance, fatty liver disease,
and type-2 diabetes (T2D) in addition to related conditions such as heart disease, asthma, cancer, and stroke.
To help control this epidemic, it will be critical to understand the specific roles of key immune cells which regulate
or exacerbate inflammation and metabolic disease in obese patients.
While many of the B cells resident in lean adipose tissue are IL-10-producing B regulatory cells (Breg), B
cell numbers increase in adipose tissue of obese mice and may play a role in the chronic inflammation
characteristic of obese visceral adipose tissue (VAT). Combined alterations in B cell antigen presentation,
cytokine profile, and antibody repertoire during obesity in mice and T2D in humans likely contributes to metabolic
disease by supporting T cell mediated-inflammation and insulin resistance; however, the cause of VAT B cell
dysregulation during obesity or T2D remains unknown. iNKT cells also make up 10-20% of T cells in healthy
adipose tissue but this proportion is reduced in obese mice and humans. Activation of the remaining iNKT cells
by the glycolipid agonist, aGalactosylceramide (aGalCer), reduces many of the inflammatory symptoms of
obesity, suggesting their loss is another important contributor to the dysregulated immune environment evident
during obesity or related autoimmune or inflammatory diseases.
We have shown that aGalCer-activated murine iNKT cells directly interact with splenic B cells to produce
antigen-specific IgG and expand IL-10+ Breg cells. Interestingly, we also see that activated iNKT cells can mediate
a similar increase in IL-10+ Breg cells in VAT, suggesting they play a key role in maintaining adipose homeostasis.
In a related murine model of chronic inflammation, we find that iNKT cells can also be licensed by neutrophils to
regulate autoreactive B cells in spleen, but the influence of neutrophils on iNKT cells and their downstream
effects on B cells in adipose tissue remains as yet uncharacterized. We hypothesize that an early neutrophil
influx educates iNKT cells in adipose tissue of obese mice to drive a pathogenic shift from Breg to B effector cells.
iNKT cell activation may also reduce metabolic disease during obesity in part by re-establishing a healthy
regulatory B cell population. These studies will enhance our understanding of key regulatory immune cell
populations in healthy and chronically inflamed obese adipose tissue with implications for many other
inflammatory diseases and related conditions such as T2D, cancer, and stroke.