The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit combined with gp130, a common receptor chain utilized by several cytokines, including IL-6. Interestingly, the IL-27 subunits p28 and EBI3 are not always co-expressed, suggesting that they may have unique functions. Here, we show IL-27p28, independent of EBI3 antagonized cytokine signaling through gp130 and IL-6 mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. IL-27p28 transgenic mice showed a major defect in germinal center formation and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.

Previous studies have implicated T cell production of IL-17 in resistance to T. gondii as well as the development of immune mediated pathology during this infection. Analysis of C57BL/6 and C57BL/6 RAG-/- mice challenged with T. gondii identified NK cells as a major innate source of IL-17. The ability of soluble toxoplasma antigen to stimulate NK cells to produce IL-17 was dependent on the presence of accessory cells and the production of IL-6, IL-23 and TGF-β. In contrast, these events were inhibited by IL-2, IL-15 and IL-27. Given that IL-6 was one of the most potent enhancers of NK cell production of IL-17, further studies revealed that only a subset of NK cells expressed both chains of the IL-6R, IL-6 upregulated expression of the Th17 associated transcription factor RORγt, and IL-6-/- mice challenged with T. gondii had a major defect in NK cell production of IL-17. Together, these data indicate that many of the same cytokines that regulate Th17 cells are part of a conserved pathway that also control innate production of IL-17 and identify a major role for IL-6 in the regulation of NK cell responses.

Active-specific immunotherapy with dendritic cells loaded with peptide derived from the melanoma antigen, gp100, failed to mediate regression of established B16F10 melanoma in normal mice. Dendritic cell vaccination induced activation and subsequent deletion of adoptively transferred naive CD8 + T-cell receptor transgenic (pmel-1) T cells specific for gp100 in normal mice. In lymphodepleted mice, dendritic cell vaccination produced greater T-cell expansion, long-term persistence of memory T cells, and tumor regression. Most tumors that persisted in the presence of functional memory T cells had either lost or exhibited reduced expression of MHC class I or gp100 proteins. In contrast to other naive T cells, pmel-1 T cells adoptively transferred to lymphodepleted mice exhibited faster proliferation and a more differentiated phenotype after exposure to peptide-pulsed dendritic cells. Proliferation and persistence of pmel-1 T cells was highly dependent on interleukin-7 (IL-7) in irradiated mice, and IL-15 when IL-7 was neutralized, two critical homeostatic cytokines produced in response to the irradiation-induced lymphodepletion. (Cancer Res 2005; 65(22): 10569-77)

IL-27 is a cytokine that regulates Th function during autoimmune and pathogen-induced immune responses. Although previous studies have shown that T regulatory cells (Treg) express the IL-27R, and that IL-27 inhibits forkhead box P3 upregulation in vitro, little is known about how IL-27 influences Treg in vivo. The studies presented here show that mice that over-express IL-27 had decreased Treg frequencies and developed spontaneous inflammation. While IL-27 did not cause mature Treg to downregulate forkhead box P3, transgenic over-expression in vivo limited the size of a differentiating Treg population in a bone marrow chimera model, which correlated with reduced production of IL-2, a vital cytokine for Treg maintenance. Together, these data identify an indirect role for IL-27 in shaping the Treg pool.

Background: In vivo studies have recently demonstrated that interleukin 21 (IL-21) enhances the anti-tumor function of T-cells and NK cells in murine tumor models, and the combined use of IL-21 and IL-15 has resulted in prolonged tumor regression and survival in mice with previously established tumors. However, the combined anti-tumor effects of IL-21 and low dose IL-2 have not been studied even though IL-2 has been approved for human use, and, at low dose administration, stimulates the proliferation of memory T cells, and does not significantly increase antigen-induced apoptosis or regulatory T cell (Treg) expansion. This study examined whether recombinant IL-21 alone or in combination with low-dose IL-2 could improve the in vivo anti-tumor function of naïve, tumor-antigen specific CD8 + T cells in a gp100 [25][26][27][28][29][30][31][32][33] T cell receptor transgenic pmel murine melanoma model.

Rationale Decision-making is a complex cognitive process that is mediated, in part, by subregions of the medial prefrontal cortex (PFC). Decision-making is impaired in a number of psychiatric conditions including schizophrenia. Notably, people with schizophrenia exhibit reductions in GABA function in the same PFC areas that are implicated in decision-making. For example, expression of the GABA-synthesizing enzyme GAD67 is reduced in the dorsolateral PFC of people with schizophrenia. Objectives The goal of this experiment was to determine whether disrupting cortical GABA transmission impairs decision-making using a rodent gambling task (rGT). Methods Rats were trained on the rGT until they reached stable performance and then were implanted with guide cannulae aimed at the medial PFC. Following recovery the effects of intra-PFC infusions of the GABAA receptor antagonist bicuculline methiodide (BMI) or the GABA synthesis inhibitor L-allylglycine (LAG) on performance on the rGT were assessed. Results Intra-cortical infusions of BMI (25 ng/μl/side), but not LAG (10 μg/μl/side), altered decision-making. Following BMI infusions, rats made fewer advantageous choices. Follow-up experiments suggested that the change in decision-making was due to a change in the sensitivity to the punishments, rather than a change in the sensitivity to reward magnitudes, associated with each outcome. LAG infusions increased premature responding, a measure of response inhibition, but did not affect decision-making. Conclusions Blocking GABAA receptors, but not inhibiting cortical GABA synthesis, within the medial PFC affects decision-making in the rGT. These data provide proof-of-concept evidence that disruptions in GABA transmission can contribute to the decision-making deficits in schizophrenia.

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IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population.