Tipping the balance

Natural killer T (NKT) cells are a subset of T cells that express both T-cell and NK-cell markers. In contrast to conventional T cells, NKT cells express semi-invariant, self-reactive antigen receptors, and they recognize glycolipid antigen in the context of the major histocompatibility complex (MHC)-like molecule CD1d. Previous studies have indicated an association between reduced numbers of NKT cells and the development of autoimmune diseases. Two groups now report in Nature Medicine that stimulation of NKT cells in non-obese diabetic (NOD) mice with α-galactosylceramide (αGC) — a glycolipid isolated from marine sponges, which is a potent stimulator of NKT cells — can prevent the development of type 1 diabetes (T1D).

T1D is, like other autoimmune diseases, thought to be mediated by pathogenic T-helper type 1 (T_H1) cells, and is associated with a defect in regulatory T cells. NOD mice, which spontaneously develop diabetes, and patients with T1D have reduced numbers of NKT cells and defects in interleukin-4 (IL-4) production (a cytokine that is necessary for the development of T_H2 responses). Previous work had shown that αGC stimulation of NKT cells leads to the development of T_H2 responses. Furthermore, increasing the number of NKT cells prevented diabetes in NOD mice. On the basis of this previous work, the two groups decided to investigate the effect of αGC on the development of diabetes in NOD mice.

Both groups showed that administration of αGC to NOD mice inhibited the development of diabetes in a dose-dependent manner, particularly when treatment was initiated at an early age. So, how does αGC inhibit the development of diabetes? The precise mechanism of action of αGC has been an issue of some debate, but in these two studies, αGC seems to stimulate NKT cells to tip the balance away from a pathogenic T_H1 response towards the development of protective T_H2 cells. Disease prevention was associated with reduced interferon-γ production and elevated serum immunoglobulin E levels. When NOD mice were crossed with CD1d-deficient mice, αGC could not prevent the development of diabetes, indicating that αGC modulates diabetes by activating NKT cells in a CD1d-dependent manner.

Sharif et al. also showed that αGC treatment prolonged the survival of islet transplants in newly diabetic NOD mice. In addition, they showed that, under conditions in which αGC alone could not prevent diabetes, IL-7 could act synergistically with αGC to prevent the onset of diabetes. The researchers suggest that IL-7 acts by restoring normal NKT cell maturation and function in NOD mice, so that αGC treatment is more effective.

Although αGC is hepatotoxic in mice, the toxicity in humans is not so severe, and it might be possible to develop αGC analogues with reduced toxicity. Furthermore, as the NKT cell response to αGC is conserved in mice and humans, these results indicate that αGC might be a useful therapy for the treatment of T1D and other T_H1-mediated autoimmune diseases.