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 + CD8b -(CD4 + ) and CD4 -CD8b -(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 a-galactosylceramide (a-GalCer)-loaded DC immediately produced massive amounts of IL-4 and IL-13, which together with IFN-c 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 crosstalk governing the Th1/2 balance and the diverse influences of iNKT cells in various diseases.

Bisphenol A (BPA) is a monomer used in manufacturing a wide range of chemical products, including epoxy resins and polycarbonate. BPA, an important endocrine disrupting chemical that exerts estrogen-like activities, is detectable at nanomolar levels in human serum worldwide. The pregnancy associated doses of 17b-estradiol (E2) plus tumor-necrosis factor-a (TNF-a) induce distorted maturation of human dendritic cells (DCs) that result in an increased capacity to induce T helper (Th) 2 responses. The current study demonstrated that the presence of BPA during DC maturation influences the function of human DCs, thereby polarizing the subsequent Th response. In the presence of TNF-a, BPA treatment enhanced the expression of CC chemokine ligand 1 (CCL1) in DCs. In addition, DCs exposed to BPA/TNF-a produced higher levels of IL-10 relative to those of IL-12p70 on CD40 ligation, and preferentially induced Th2 deviation. BPA exerts the same effect with E2 at the same dose (0.01-0.1 mM) with regard to DC-mediated Th2 polarization. These findings imply that DCs exposed to BPA will provide one of the initial signals driving the development and perpetuation of Th2-dominated immune response in allergic reactions.

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CD1d-restricted invariant NKT (iNKT) cells play crucial roles in various types of immune responses, including autoimmune diseases, infectious diseases and tumor surveillance. The mechanisms underlying their adjuvant functions are well understood. Nevertheless, although IL-4 and IL-10 production characterize iNKT cells able to prevent or ameliorate some autoimmune diseases and inflammatory conditions, the precise mechanisms by which iNKT cells exert immune regulatory function remain elusive. This study demonstrates that the activation of human iNKT cells by their specific ligand α-galactosylceramide enhances IL-12p70 while inhibiting the IL-23 production by monocyte-derived dendritic cells, and in turn down-regulating the IL-17 production by memory CD4+ Th cells. The ability of the iNKT cells to regulate the differential production of IL-12p70/IL-23 is mainly mediated by a remarkable hallmark of their function to produce both Th1 and Th2 cytokines. In particular, the down-regulation of IL-23 is markedly associated with a production of IL-4 and IL-10 from iNKT cells. Moreover, Th2 cytokines, such as IL-4 and IL-13 play a crucial role in defining the biased production of IL-12p70/IL-23 by enhancement of IL-12p70 in synergy with IFN-γ, whereas inhibition of the IFN-γ-promoted IL-23 production. Collectively, the results suggest that iNKT cells modify the IL-12p70/IL-23 balance to enhance the IL-12p70-induced cell-mediated immunity and suppress the IL-23-dependent inflammatory pathologies. These results may account for the long-appreciated contrasting beneficial and adverse consequence of ligand activation of iNKT cells.

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The molecular and cellular mechanisms that generate the T(h)2 cytokine environment necessary for the maintenance of pregnancy are still not fully understood. We herein show that the human decidua is highly enriched for TCR alpha beta(+)CD161(+) NKT cells. They express non-invariant antigen receptors encoded by diverse TCRV alpha- and V beta-chain gene segments, thereby referred to as non-invariant NKT (non-iNKT) cells. In spite of their diverse TCR expression, they do not recognize fetal allo-antigens but specifically responded to CD1d-transfected cell lines. In contrast to the peripheral blood non-iNKT cells, the decidua-residing non-iNKT cells had a marked T(h)2 bias. In addition, they suppress the mixed leukocyte reaction directed against the paternal antigens. The T(h)2 cytokines have been known to stimulate trophoblast outgrowth and invasion. Thereby, the non-iNKT cells residing in the decidual tissue may have a functionally important interaction with the villous and extravillous trophoblast cells expressing CD1d and may therefore play a pivotal role in successful pregnancy by inhibiting fetal rejection and enhancing placental growth. These findings may reflect one mechanism that is an essential component for the T(h)2 environment necessary for the maintenance of pregnancy.