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Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs promote tumor growth by inhibiting anti-cancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8+T cells required for the induction of experimental autoimmune diabetes. Their major suppression mechanism is limiting available IL-2, an essential T-cell cytokine. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated KLRK1+IL7R+(KILR) CD8+effector T cells, which are distinct from conventional effector CD8+T cells. KILR CD8+T cells show a superior cell killing abilities in vivo. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces KILR CD8+T cells, promotes autoimmunity, and enhances anti-tumor responses. Counterparts of KILR CD8+T cells were found in the human blood, revealing them as a potential target for immunotherapy.

The kynurenine (KYN) pathway (KP) is a major degradative pathway of the amino acid, l-tryptophan (TRP), that ultimately leads to the anabolism of the essential pyridine nucleotide, nicotinamide adenine dinucleotide. TRP catabolism results in the production of several important metabolites, including the major immune tolerance-inducing metabolite KYN, and the neurotoxin and excitotoxin quinolinic acid. Dendritic cells (DCs) have been shown to mediate immunoregulatory roles that mediated by TRP catabolism. However, characterization of the KP in human DCs has so far only been partly delineated. It is critical to understand which KP enzymes are expressed and which KP metabolites are produced to be able to understand their regulatory effects on the immune response. In this study, we characterized the KP in human monocyte-derived DCs (MDDCs) in comparison with the human primary macrophages using RT-PCR, high-pressure gas chromatography, mass spectrometry, and immunocytochemistry. Our results show that the KP is entirely expressed in human MDDC. Following activation of the KP using interferon gamma, MDDCs can mediate apoptosis of T h cells in vitro. Understanding the molecular mechanisms regulating KP metabolism in MDDCs may provide renewed insight for the development of novel therapeutics aimed at modulating immunological effects and peripheral tolerance.

The kynurenine (KYN) pathway (KP) is a major degradative pathway of the amino acid, L-tryptophan (TRP), that ultimately leads to the anabolism of the essential pyridine nucleotide, nicotinamide adenine dinucleotide. TRP catabolism results in the production of several important metabolites, including the major immune tolerance-inducing metabolite KYN, and the neurotoxin and excitotoxin quinolinic acid. Dendritic cells (DCs) have been shown to mediate immunoregulatory roles that mediated by TRP catabolism. However, characterization of the KP in human DCs has so far only been partly delineated. It is critical to understand which KP enzymes are expressed and which KP metabolites are produced to be able to understand their regulatory effects on the immune response. In this study, we characterized the KP in human monocyte-derived DCs (MDDCs) in comparison with the human primary macrophages using RT-PCR, high-pressure gas chromatography, mass spectrometry, and immunocytochemistry. Our results show that the KP is entirely expressed in human MDDC. Following activation of the KP using interferon gamma, MDDCs can mediate apoptosis of T

Background Cachexia is a complex syndrome defined by weight loss due to an ongoing loss of skeletal muscle mass with or without loss of body fat. It is often associated with anorexia. Numerous results from experimental studies suggest that blockade of the melanocortin-4 receptor (MC4R) could be an effective treatment for anorexia and cachexia. In a previous study, we reported the basic pharmacological properties of a blocking anti-MC4R mAb 1E8a and its scFv derivative in vitro and in vivo. Methods In the present study, we further characterized the mode of action of the 1E8a scFv, evaluated its pharmacokinetic properties in mice, and assessed its therapeutic potential in a lipopolysaccharide (LPS)-induced cachexia model in rats. Results In vitro, scFv enhanced the efficacy of the endogenous inverse agonist Agouti-related protein. After intravenous (i.v.) administration in mice, the scFv penetrated the blood–brain barrier (BBB) and reached its central sites of action: the scFv brain–serum concentration ratios increased up to 15-fold which suggests an active uptake into brain tissue. In telemetry experiments, i.v. administration of the scFv in rats was well tolerated and only induced slight cardiovascular effects consistent with MC4R blockade, i.e., a small decrease in mean arterial pressure and heart rate. In the model of LPS-induced anorexia, i.v. administration of scFv 1E8a prevented anorexia and loss of body weight. Moreover, it stimulated a myogenic response which may contribute to the preservation of muscle mass in cachexia. Conclusion The pharmacological profile of scFv 1E8a suggests its potential value in the treatment of cachexia or anorexia.