Inhibition of T Helper Cell Type 2 Cell Differentiation and Immunoglobulin E Response by Ligand-Activated Vα14 Natural Killer T Cells

Abstract

Murine Vα14 natural killer T (NKT) cells are thought to play a crucial role in various immune responses, including infectious, allergic, and autoimmune diseases. Because Vα14 NKT cells produce large amounts of both interleukin (IL)-4 and interferon (IFN)-γ upon in vivo stimulation with a specific ligand, α-galactosylceramide (α-GalCer), or after treatment with anti-CD3 antibody, a regulatory role on helper T (Th) cell differentiation has been proposed for these cells. However, the identity of the cytokine produced by Vα14 NKT cells that play a dominant role on the Th cell differentiation still remains controversial. Here, we demonstrate by using Vα14 NKT-deficient mice that Vα14 NKT cells are dispensable for the induction of antigen-specific immunoglobulin (Ig)E responses induced by ovalbumin immunization or Nippostrongylus brasiliensis infection. However, upon in vivo activation with α-GalCer, Vα14 NKT cells are found to suppress antigen-specific IgE production. The suppression appeared to be IgE specific, and was not detected in either Vα14 NKT– or IFN-γ–deficient mice. Consistent with these results, we also found that ligand-activated Vα14 NKT cells inhibited Th2 cell differentiation in an in vitro induction culture system. Thus, it is likely that activated Vα14 NKT cells exert a potent inhibitory effect on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-γ. In marked contrast, our studies have revealed that IL-4 produced by Vα14 NKT cells has only a minor effect on Th2 cell differentiation.

Costimulation-Dependent Modulation of Experimental Autoimmune Encephalomyelitis by Ligand Stimulation of Vα14 NK T Cells

“…This study was initiated to explore whether EAE can be treated with ␣-GC capable of stimulating NK T cells in vivo. Because ligand-activated NK T cells exhibited immunoregulatory activities in previous studies (25)(26)(27), This table summarizes we expected that the disease could be modified by administration of ␣-GC. However, an injection of ␣-GC modulated EAE in the wild-type mice only slightly in the enhancement of cumulative disease scores.…”

“…However, opposing theories have been provided regarding the possible effect of ␣-GC on immune-mediated diseases. Cui et al (25) speculated a therapeutic effect of ␣-GC for Th2 cell-mediated diseases based on its potential to induce IFN-␥ production by NK T cells, whereas other studies (26,27) indicate that ␣-GC induces a Th2 shift of NK T cells and is effective for treatment of Th1-mediated diseases. However, none of these have examined the effect of ␣-GC on autoimmune disease models.…”

Invariant Vα14+ NKT Cells Participate in the Early Response to EntericListeria monocytogenesInfection

“…22). V␣14 ϩ NKT cells could provide a protective role via IFN-␥ in sustaining Th1 responses (23). Alternatively, IL-4 production from V␣14 ϩ NKT cells could either have a deleterious role by deviating Th1 responses toward Th2 or act as an amplifier of Th2 responses in the context of extracellular parasites (24,25).…”

Selective Loss of Natural Killer T Cells by Apoptosis following Infection with Lymphocytic Choriomeningitis Virus

“…It has been suggested that this prompt production of IL-4 by NKT cells plays an important role in the induction of Th2-mediated responses (37,67), although in some systems, it appears that this is not the case (10,15,56). An important role for IFN-␥ production by NKT cells has been found in the immune response to Nippostrongylus brasiliensis (15), Toxoplasma gondii (16), and Plasmodium yoelii (24).…”

“…In support of this, it has been shown that in scleroderma and diabetes, a lack of (or reduction in) NKT-cell number and/or function contributes to the development of these diseases (23,29,37,59,65). It has been suggested that this prompt production of IL-4 by NKT cells plays an important role in the induction of Th2-mediated responses (37,67), although in some systems, it appears that this is not the case (10,15,56). An important role for IFN-␥ production by NKT cells has been found in the immune response to Nippostrongylus brasiliensis (15), Toxoplasma gondii (16), and Plasmodium yoelii (24).…”