[91, 92] This C20:2 induced shorter duration of type I NKT cells in the anergic state promotes the more rapid induction of tolerogenic DCs in an IL-10-dependent manner, gives rise to reduced type I NKT cell

death, and enables C20:2-stimulated type I NKT cells to elicit enhanced protection from type 1 diabetes. These findings suggest that C20:2 may be more effective for disease intervention than αGalCer for protection from type 1 diabetes. It is anticipated AZD3965 purchase that further support for this possibility could be obtained by more informative in vivo imaging studies of the dynamics and kinetics of interaction between type I NKT cells and DCs in pancreatic lymph nodes of NOD mice treated in vivo with either αGalCer or C20:2. In addition, 2P imaging in vivo of differentially activated and anergic NKT cells will further elucidate how a short versus long duration of NKT cell anergy can regulate poor versus strong protection from type 1 diabetes. In a second model, 2P imaging may offer more insight into whether C24:0 sulphatide activates type II NKT cells to enter into and exit from anergy more rapidly than C16:0 sulphatide activation and thereby yield less type II NKT cell death and increased CH5424802 manufacturer protection from T1D.[89] Finally, a third model is based on the report that activation of sulphatide-reactive type II NKT cells and DCs elicits the IL-12- and macrophage inflammatory protein

2-dependent recruitment of type I NKT cells into the liver.[62] The latter recruited type I NKT cells are anergic and prevent concanavalin A (Con A) -induced hepatitis by specifically blocking effector pathways, including the cytokine burst and neutrophil recruitment following Con A injection. Hepatic DCs from IL-12+/+ but not from IL-12−/− mice can adoptively transfer type I NKT cell anergy into recipient mice. Hence, IL-12 secretion by DCs enables them to induce anergy in type I NKT cells. These data describe a novel mechanism by which type II NKT cell–DC interactions in the liver can cross-regulate the activity of type I NKT cells. Further in vivo imaging analyses may help

to demonstrate whether this type of immune cross-regulation applies to human NKT cell subsets. If this is PtdIns(3,4)P2 the case, such studies may facilitate immune intervention in inflammatory and autommmune diseases in humans. The ability to detect intracellular signalling that occurs during T-cell–DC contacts by 2P imaging in vivo has dramatically improved our understanding of cellular communication during immune responses.[51, 54] While a brief contact of T cells with antigen-bearing DCs induces T cells to pause momentarily and then continue their migration, these T-cell–DC interactions also induce Ca2+ signalling in T cells that promptly reduces T-cell motility. The Ca2+ signals may synergize with other signalling pathways to stimulate T-cell gene expression, cytokine secretion and proliferation.