The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells

Abstract

OCH, a sphingosine-truncated analog of α-galactosylceramide (αGC), is a potential therapeutic reagent for a variety of Th1-mediated autoimmune diseases through its selective induction of Th2 cytokines from natural killer T (NKT) cells. We demonstrate here that the NKT cell production of IFN-γ is more susceptible to the sphingosine length of glycolipid ligand than that of IL-4 and that the length of the sphingosine chain determines the duration of NKT cell stimulation by CD1d-associated glycolipids. Furthermore, IFN-γ production by NKT cells requires longer T cell receptor stimulation than is required for IL-4 production by NKT cells stimulated either with immobilized mAb to CD3 or with immobilized "αGC-loaded" CD1d molecules. Interestingly, transcription of IFN-γ but not that of IL-4 was sensitive to cycloheximide treatment, indicating the intrinsic involvement of de novo protein synthesis for IFN-γ production by NKT cells. Finally, we determined c-Rel was preferentially transcribed in αGC-stimulated but not in OCH-stimulated NKT cells and was essential for IFN-γ production by activated NKT cells. Given the dominant immune regulation by the remarkable cytokine production of ligand-stimulated NKT cells in vivo, in comparison with that of (antigen-specific) T cells or NK cells, the current study confirms OCH as a likely therapeutic reagent for use against Th1-mediated autoimmune diseases and provides a novel clue for the design of drugs targeting NKT cells.

Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre‐eclampsia may be mediated by natural killer cells

“…NKT cells have the unique potential to produce large amounts of cytokines within minutes of activation 44, more per cell than NK cells or antigen‐specific T cells 45, 46. NKT cells are the lymphocytes most likely to be the subset spontaneously producing cytokines in peripheral blood 47] and appear to play a dominant role in immune regulation 48. Their in vivo stimulation leads to activation of both innate and acquired immunity in humans 49.…”

Modulation of Vα19 NKT cell immune responses by α‐mannosyl ceramide derivatives consisting of a series of modified sphingosines

“…The altered interaction between the modified α‐ManCer and MR1 could presumably influence the spatial location of the α‐mannosyl residue to be recognized by the invariant Vα19 TCR and eventually result in the modulation of the immune responses of Vα19 NKT cells. Induction of Th2‐biased immune responses of Vα14 NKT cells with the α‐GalCer consisting of a short sphingosine base has been reported 21. It is proposed in the report that the sporadic stimulation of the invariant Vα14 TCR with the galactose residue of the modified α‐GalCer causes insufficient transcription of c‐Rel, which is responsible for the expression of Th1 cytokines such as IFN‐γ 22.…”

The involvement of Vα14 natural killer T cells in the pathogenesis of arthritis in murine models

“…We showed, in this study, that mice deficient in V α 14 NKT cells exhibited a reduced severity of antibody‐mediated arthritis, suggesting that V α 14 NKT cells act as effector cells in inflammatory arthritis. Potential V α 14 NKT cell effector mechanisms that may be important for the induction and progression of joint inflammation include the rapid production of a variety of cytokines, including IL‐1 and TNFα, that play a critical role in both K/BxN serum–induced arthritis and anti‐CII mAb–induced arthritis, as well as in human RA (1, 30, 31, 34). Very recently, Kim et al reported that NKT cells promote K/BxN serum–induced joint inflammation by producing IL‐4 and IFNγ (35).…”