Distinct subsets of human invariant NKT cells differentially regulate T helper responses via dendritic cells

Invariant natural killer T (iNKT) cells regulate the T helper (Th) 1/2 balance and elicit either enhancement or suppression of the immune responses. However, the exact mechanism by which iNKT cells exert these contrasting functions has remained elusive. We demonstrate herein that two major distinct subsets of human iNKT cells, CD4+CD8beta(-) (CD4+) and CD4(-)CD8beta(-) (double negative; DN) cells, express functional CD40 ligand (CD40L), but they differentially regulate the dendritic cell (DC) function by reciprocal NKT-DC interactions, thereby influencing the subsequent Th response. The CD4 subset stimulated by alpha-galactosylceramide (alpha-GalCer)-loaded DC immediately produced massive amounts of IL-4 and IL-13, which together with IFN-gamma enhanced CD40L-induced IL-12 production by DC. In contrast, the DN subset eliminated the DC by cytolysis and changed the living DC into a default subtype, in turn markedly down-regulating the levels of IL-12. Therefore, the DC stimulated by the CD4 subset preferentially induced Th1 responses, whereas the DC reacted with the DN subset induced a shift toward Th2 responses. These findings may provide an important insight into better understanding the contribution of iNKT-DC cross-talk governing the Th1/2 balance and the diverse influences of iNKT cells in various diseases.