Main applicant: Eric Kalkhoven; co-applicant: Marianne Boes.
The profile and activity of adipose tissue (AT)-resident immune cells plays a key role in the prevention of insulin resistance and type 2 diabetes. A branch of the immune system that was largely overlooked until very recently are the CD1d-restricted invariant (i)Natural Killer T (NKT) cells, a unique subset of lymphocytes that are reactive to socalled lipid antigens. AT-resident iNKT cells may be protective against the development of insulin resistance, as (i) in humans AT-resident iNKT cell numbers correlate negatively with BMI, and (ii) mice which specifically lack iNKT cells spontaneously develop insulin resistance without being challenged by HFD feeding. In addition, we and others reported that adipocytes can function as non-professional antigen-presenting cells (APC) for iNKT cells, illustrated by co-culture experiments. Together, these findings raise the fascinating concept that adipocytes, harboring stored lipids with potential antigenic properties, can directly stimulate local iNKT cells and maintain healthy adipose tissue, thereby preventing the development of type 2 diabetes. However, endogenous lipid antigen presentation by adipocytes is currently poorly understood. Using a combination of cell based assays, lipidomics and human studies we propose to delineate these pathways and establish whether modulation of lipid antigen presentation represents a potential approach for the prevention and therapeutic treatment of type 2 diabetes.