Endogenous lipid antigens for invariant natural killer T cells hold the reins in adipose tissue homeostasis

Summary The global obesity epidemic and its associated co‐morbidities, including type 2 diabetes, cardiovascular disease and certain types of cancers, have drawn attention to the pivotal role of adipocytes in health and disease. Besides their ‘classical’ function in energy storage and release, adipocytes interact with adipose‐tissue‐resident immune cells, among which are lipid‐responsive invariant natural killer T (iNKT) cells. The iNKT cells are activated by lipid antigens presented by antigen‐presenting cells as CD1d/lipid complexes. Upon activation, iNKT cells can rapidly secrete soluble mediators that either promote or oppose inflammation. In lean adipose tissue, iNKT cells elicit a predominantly anti‐inflammatory immune response, whereas obesity is associated with declining iNKT cell numbers. Recent work showed that adipocytes act as non‐professional antigen‐presenting cells for lipid antigens. Here, we discuss endogenous lipid antigen processing and presentation by adipocytes, and speculate on how these lipid antigens, together with ‘environmental factors’ such as tissue/organ environment and co‐stimulatory signals, are able to influence the fate of adipose‐tissue‐resident iNKT cells, and thereby the role of these cells in obesity and its associated pathologies. Extensive communication between adipocytes and immune cells, including invariant natural killer T (iNKT) cells, contributes importantly to metabolic health and disease. Endogenous lipid antigens presented by adipocytes together with ‘environmental factors’ such as tissue/organ environment and co‐stimulatory signals, can influence the fate of iNKT cells, and thereby the role of these cells in obesity and its associated pathologies.