A novel lymphocyte lineage, Valpha14 natural killer T (NKT) cells, is now well established as distinct from conventional alphabeta T cells. Valpha14 NKT cells express a single invariant Valpha14 antigen receptor that is essential for their development. Successful identification of a specific ligand, alpha-galactosylceramide(alpha-GalCer), and the establishment of gene-manipulated mice with selective loss of Valpha14 NKT cells helped elucidate the remarkable functional diversity of Valpha14 NKT cells in various immune responses such as host defense by mediating anti-nonself innate immune reaction, homeostatic regulation of anti-self responses, and antitumor immunity.

The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A–induced hepatitis is considered to be an experimental model of human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that Vα14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A–activated Vα14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of Vα14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in Vα14 NKT cells. Moreover, Vα14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin–granzyme B and FasL appear to be effector molecules in Con A–induced Vα14 NKT cell–mediated hepatocyte injury.

We have recently identified ␣-galactosylceramide (␣-GalCer) as a specific ligand for an invariant V␣14͞ V␤8.2 T cell receptor exclusively expressed on the majority of V␣14 NKT cells, a novel subset of lymphocytes. Here, we report that ␣-GalCer selectively activates V␣14 NKT cells resulting in prevention of tumor metastasis. The effector mechanisms of the ligand-activated V␣14 NKT cells seem to be mediated by natural killer (NK)-like nonspecific cytotoxicity. Indeed, the cytotoxic index obtained by ␣-GalCeractivated V␣14 NKT cells was reduced by the addition of cold target tumor cells or by treatment with concanamycin A, which inhibits activation and secretion of perforin, but not by mAbs against molecules involved in the NKT cell recognition and conventional cytotoxicity, such as CD1d, V␤8, NK1.1, Ly49C, Fas, or Fas ligand. These results suggest that the ligand-activated V␣14 NKT cells kill tumor cells directly through a CD1d͞V␣14 T cell receptor-independent, NK-like mechanism.A novel lymphoid lineage, V␣14 natural killer (NK) T cells, distinct from other lymphoid cells including T cells, B cells, and NK cells, is characterized by the early development at day 9.5 of gestation before thymus formation (1) and also by coexpression of the NK receptor and a single, invariant T cell receptor (TCR) encoded by V␣14 and J␣281 gene segments (2-4) in association with a highly skewed set of V␤s, mainly V␤8.2 (5-13). Moreover, the generation of V␣14 NKT cells is exclusively dependent on the expression of the invariant V␣14 TCR as evidenced by the fact that V␣14 NKT cells do not develop in the invariant V␣14 TCR-deficient mice (14) and that the forced expression of the invariant V␣14 TCR leads exclusively to V␣14 NKT cell generation and blocks conventional T cell development (15, 16).Although physiological functions of V␣14 NKT cells remain to be elucidated, the extensive analysis has shown that V␣14 NKT cells are able to mediate allograft bone marrow rejection (17), control autoimmune disease development (18,19), and produce large amounts of both interleukin 4 (IL-4) and interferon ␥ (16,20,21). These findings suggest that V␣14-NKT cells play complicated roles in regulating immune responses more than simply as IL-4 or interferon ␥ providers for Th2 or Th1 cell development, respectively, so far reported (22,23). In addition, we have demonstrated recently that V␣14 NKT cells are a primary target of IL-12 and exert a major effector function in IL-12-mediated tumor rejection (14).A ligand for the invariant V␣14͞V␤8.2 TCR exclusively expressed on V␣14 NKT cells has been identified recently to be ␣-galactosylceramide (␣-GalCer) (16). In addition, ␣-GalCer is presented by a monomorphic non-majorhistocompatibility gene complex (non-MHC) class Ib molecule, CD1d, expressed on dendritic cells (DC), and the ligand͞CD1 complex selectively stimulates to proliferate V␣14 NKT cells but not other lymphocytes only if costimulatory signals generated by CD40͞CD40 ligand and B7͞ CD28 interactions are provided (16). The results suggest th...

BACKGROUND The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids. METHODS We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects. RESULTS We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P = 0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P = 0.0007 for pooled data). Overall, the mean (± SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2 ± 1.6% vs. 9.4 ± 1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability. CONCLUSIONS A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00000575.)