Obesity triggers a low-grade systemic inflammation, which plays an important role in the development of obesity-associated metabolic diseases. In searching for links between lipid accumulation and chronic inflammation, we examined invariant natural killer T (iNKT) cells, a subset of T lymphocytes that react with lipids and regulate inflammatory responses. We show that iNKT cells respond to dietary lipid excess and become activated before or at the time of tissue recruitment of inflammatory leukocytes, and that these cells progressively increase proinflammatory cytokine production in obese mice. Such iNKT cells skew other leukocytes toward proinflammatory cytokine production and induce an imbalanced proinflammatory cytokine environment in multiple tissues. Further, iNKT cell deficiency ameliorates tissue inflammation and provides protection against obesity-induced insulin resistance and hepatic steatosis. Conversely, chronic iNKT cell stimulation using a canonical iNKT cell agonist exacerbates tissue inflammation and obesityassociated metabolic disease. These findings place iNKT cells into the complex network linking lipid excess to inflammation in obesity and suggest new therapeutic avenues for obesity-associated metabolic disorders.cluster of differentiation 1d | glycolipid-reactive T cells | alpha-galactosylceramide | obesity-induced inflammation

Endoplasmic reticulum (ER)-associated aminopeptidase (ERAP)1 has been implicated in the final proteolytic processing of peptides presented by major histocompatibility complex (MHC) class I molecules. To evaluate the in vivo role of ERAP1, we have generated ERAP1-deficient mice. Cell surface expression of the class Ia molecules H-2Kb and H-2Db and of the class Ib molecule Qa-2 was significantly reduced in these animals. Although cells from mutant animals exhibited reduced capacity to present several self- and foreign antigens to Kb-, Db-, or Qa-1b–restricted CD8+ cytotoxic T cells, presentation of some antigens was unaffected or significantly enhanced. Consistent with these findings, mice generated defective CD8+ T cell responses against class I–presented antigens. These findings reveal an important in vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules.

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Peptide immunotherapy both activates and suppresses the T cell response against known peptide Ags. Although pretreatment with VP2121–130 peptide inhibits the development of antiviral CTL specific for the immunodominant Db:VP2121–130 epitope expressed during acute Theiler’s murine encephalomyelitis virus infection, i.v. injection of this same peptide or MHC tetramers containing the peptide during an ongoing antiviral CTL response results in a peptide-induced fatal syndrome (PIFS) within 48 h. Susceptibility to PIFS is dependent on peptide-specific CD8+ T cells, varies among inbred strains of mice, and is not mediated by traditionally defined mechanisms of shock. Analyses using bone marrow chimeras and mutant mice demonstrate that susceptibility to PIFS is determined by the genotype of bone marrow-derived cells and requires the expression of perforin. Animals responding to peptide treatment with PIFS develop classical stress responses in the brain. These findings raise important considerations for the development of peptide therapies for active diseases to modify immune responses involving expanded populations of T cells. In summary, treatment with peptides or MHC-tetramers during a peptide-specific immune response can result in a fatal shock-like syndrome. Susceptibility to the syndrome is genetically determined, is mediated by CD8+ T cells, and requires expression of perforin. These findings raise concerns about the use of peptides and MHC tetramers in therapeutic schemes.

Intestinal intraepithelial lymphocytes (IEL) bear a partially activated phenotype that permits them to rapidly respond to antigenic insults. However, this phenotype also implies that IEL must be highly controlled to prevent misdirected immune reactions. It has been suggested that IEL are regulated through the interaction of the CD8␣␣ homodimer with the thymus leukemia (TL) antigen expressed by intestinal epithelial cells. We have generated and characterized mice genetically-deficient in TL expression. Our findings show that TL expression has a critical role in maintaining IEL effector functions. Also, TL deficiency accelerated colitis in a genetic model of inflammatory bowel disease. These findings reveal an important regulatory role of TL in controlling IEL function and intestinal inflammation.CD8␣␣ ͉ mucosal immunity ͉ colitis ͉ nonclassical MHC ͉ immunoregulation T he intestinal mucosa represents one of the major entry points for antigens into the body, and thus requires a refined immunological system that can prevent the invasion and dissemination of both commensal and pathogenic microorganisms. One of the main immunological compartments involved in regulating mucosal immune responses is comprised by the intraepithelial lymphocytes (IEL). IEL are a population of lymphocytes that reside within the intestinal epithelium, and constitute one of the largest populations of lymphocytes in the body. In mice, 3 main subpopulations of IEL have been identified: TCR␥␦ ϩ T cells expressing mostly the CD8␣␣ homodimer, TCR␣␤ ϩ T cells expressing either CD4 or CD8␣␤ and sometimes coexpressing CD8␣␣, and TCR␣␤ ϩ T cells expressing CD8␣␣ (1). Many reports indicate that these populations function in the recognition of stress signals (2), are involved in the recovery from tissue damage (3, 4), function as conventional memory cells (1), or have natural autoreactivity, suggesting a regulatory role (5, 6). Despite their varied function and phenotype, the great majority of IEL are characterized by a ''partial activation'' state (7). This phenotype suggests that IEL are capable of rapidly responding to stimuli, and therefore, must be held in tight check to prevent unwanted reactions. Thus, an intriguing aspect is the regulation of the effector functions of IEL, which remains incompletely understood.The thymus leukemia (TL) antigen is a nonclassical MHC class I molecule encoded by a locus within the MHC complex (8). TL expression is confined to the surface of intestinal epithelial cells (IEC) (9, 10) and it does not appear to bind an antigenic moiety (11,12). Recently, it has been demonstrated that TL binds preferentially to the CD8␣␣ homodimer (11-17), and it has been suggested that this interaction, at least in vitro, modulates IEL responses.Considering that CD8␣␣ is a prevalent surface marker on IEL, and that these cells reside in close proximity to TL-expressing IEC, we hypothesized that TL has a key role in regulating IEL effector functions. In the present study, we have analyzed mice deficient in the expression of TL and report...