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

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease that can be protected against by stimulating regulatory cells. Here we examined whether EAE can be purposefully modulated by stimulating Vα14 NK T cells with the CD1d-restricted ligand α-galactosylceramide (α-GC). EAE induced in wild-type C57BL/6 (B6) mice was not appreciably altered by injection of α-GC. However, EAE induced in IL-4 knockout mice and IFN-γ knockout mice was enhanced or suppressed by α-GC, respectively. This indicates that the IL-4 and IFN-γ triggered by α-GC may play an inhibitory or enhancing role in the regulation of EAE. We next studied whether NK T cells of wild-type mice may switch their Th0-like phenotype toward Th1 or Th2. Notably, in the presence of blocking B7.2 (CD86) mAb, α-GC stimulation could bias the cytokine profile of NK T cells toward Th2, whereas presentation of α-GC by CD40-activated APC induced a Th1 shift of NK T cells. Furthermore, transfer of the α-GC-pulsed APC preparations suppressed or enhanced EAE according to their ability to polarize NK T cells toward Th2 or Th1 in vitro. These results have important implications for understanding the role of NK T cells in autoimmunity and for designing a therapeutic strategy targeting NK T cells.

Immunoregulation of Autoimmunity by Natural Killer T Cells

“…This was associated with a striking inhibition of antigen-specific IFN-γ production, but was independent of IL-4 [89]. Additionally, studies using α-GalCer induced NKT cell stimulation confirmed the capacity of NKT cells to modulate the disease by inducing Th2 cytokine profiles [90,91,92]. However, others reported that the protective effect was associated with an enhanced IFN-γ production by liver-confined NKT cells [92].…”

“…Furthermore, the efficacy of α-GalCer treatment depended on the administration route, timing and dose [93,92]. In an effort to overcome these problems, combination therapy of α-GalCer and CD86 blocking antibodies or treatment with OCH was shown to selectively induce a Th2 response by the NKT cells and resulted in a reduced development of EAE [91,94,40].…”

“…Possibly, some of the potential problems associated with α-GalCer based therapy can be overcome by the use of analogues with superior activity in inducing Th2 responses (OCH) or by combination therapies with cytokines (IL-7) or antibodies (anti-CD86 antibodies) that suppress Th1 and/or enhance Th2 cytokine production by NKT cells [105,91]. These approaches have already shown significant effect in animal models of autoimmune diseases.…”

Cytokines and effector T cell subsets causing autoimmune CNS disease

“…However, their contribution to EAE is unknown while the role of IFN-c or IL-4 producing NKT cells has been investigated in EAE. Depending on the timing and mode of their activation with aGalCer, NKT cells can exacerbate EAE [163] or downmodulate the inflammatory response [163][164][165][166]. While NKT cells home to secondary lymphoid tissue, gut associated lymphoid tissue, and liver, recruitment to the CNS is under debate [162,167,168].…”

IL‐18 time‐dependently modulates Th1/Th2 cytokine production by ligand‐activated NKT cells

“…Several reports suggest that these CD28-CD80/86-and CD154-CD40-mediated costimulatory pathways might be involved in IFN-c/IL-4 production by a-GalCer-stimulated NKT cells [14,15]. If IL-18 pretreatment affects the expression level of these costimulatory molecules, the downstream signals may regulate NKT cell function by modulating IFN-c/IL-4 production.…”