Understanding the behavior of invariant NKT cells in autoimmune diseases

Invariant NKT (iNKT) cells are a unique subset of lymphocytes that recognize glycolipid antigens presented by a monomorphic glycoprotein CD1d. Numerous works have shown that iNKT cells may serve as regulatory cells in autoimmune diseases including multiple sclerosis (MS). However, recent studies have revealed that the presence of iNKT cells accelerates some inflammatory conditions, implying that their protective role against autoimmunity is not predetermined. Here we review recent information concerning the mechanism of how iNKT cells intervene or promote autoimmune inflammation. Although iNKT cells are thought to be specific for a limited set of glycolipids, they may cross-react to self and non-self ligands. Regarding the response to non-self, it is now known that iNKT cells produce enormous amounts of proinflammatory cytokines during the course of infectious diseases, which is triggered by TCR ligation by microbial lipids, cytokines produced from APCs or both. Whereas the strongly activated iNKT cells play a beneficial role in combating environmental pathogens, they could play a deleterious role in autoimmunity by producing disease-promoting cytokines. However, iNKT cells in the steady state would retain an ability to produce anti-inflammatory cytokines, which is needed for terminating the ongoing inflammation. Though an initial trigger for their regulatory responses remains elusive, our recent work indicates that iNKT cells may start regulating inflammation after sensing the presence of IL-2 in addition to recognizing a ubiquitous endogenous ligand. Understanding of how iNKT cells regulate autoimmunity should lead to a more sophisticated strategy for controlling autoimmune diseases.