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Interleukin-10 (IL-10)-producing regulatory B ([B.sub.reg]) cells suppress autoimmune disease, and increased numbers of [B.sub.reg] cells prevent host defense to infection and promote tumor growth and metastasis by converting resting [CD4.sup.+] T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of [B.sub.reg] cells remain unclear. Here we show that IL-35 induces [B.sub.reg] cells and promotes their conversion to a [B.sub.reg] subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less [B.sub.reg] cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of [B.sub.reg] cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 ([T.sub.H]17) and [T.sub.H]1 cells while promoting [T.sub.reg] cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into [B.sub.reg] cells, these findings suggest that IL-35 may be used to induce autologous [B.sub.reg] and [IL-35.sup.+] [B.sub.reg] cells and treat autoimmune and inflammatory disease., B cell depletion is an effective therapy for a number of T cell-mediated autoimmune diseases, suggesting that B cells may contribute to autoimmunity (1-4). However, subsequent studies showed that the [...]

T-helper type 17 cells (T[sub.H]17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T[sub.H]17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-[gamma]. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-[alpha] in retinal cells, suggesting a mechanism by which T[sub.H]17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-[gamma] and inhibited proliferation of T[sub.H]17. These findings suggest that T[sub.H]1 cells may mitigate uveitis by antagonizing the T[sub.H]17 phenotype through the IFN-[gamma]-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T[sub.H]17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T[sub.H]17 by IFN-[gamma] and/or IL-27 could be used for the treatment of chronic inflammation., Author(s): Ahjoku Amadi-Obi [1, 4]; Cheng-Rong Yu [1, 4]; Xuebin Liu [1]; Rashid M Mahdi [1]; Grace Levy Clarke [2]; Robert B Nussenblatt [2]; Igal Gery [3]; Yun Sang Lee [...]

A study of the influence of the constitutive lens expression of gamma-interferon (gamma-IFN) on eye development in transgenic mice with targeted gamma-IFN expression in the lens reveals a breakdown of the retinal and lens differentiation schedules by the eighteenth day of embryonic development. mRNA levels of lens cell differentiation markers are decreased while the gamma-INF-activated-transcriptional factor ICSBP expression is promoted in the transgenic mouse eyes, indicating that lens gene expression distribution determines the course of development of cells that grow into lens fiber cells.

Nat. Med.; doi:10.1038/nm.3554; corrected online 30 May 2014 In the version of this article initially published online, there were several errors in the text and figures. Two authors' names were [...]

Interferon Regulatory Factor-8 (IRF8) is constitutively expressed in monocytes and B cell lineages and plays important roles in immunity to pathogens and cancer. Although IRF8 expression is induced in activated T cells, the functional relevance of IRF8 in T cell-mediated immunity is not well understood. In this study, we used mice with targeted deletion of Irf8 in T-cells (IRF8KO) to investigate the role of IRF8 in T cell-mediated responses during herpes simplex virus 1 (HSV-1) infection of the eye. In contrast to wild type mice, HSV-1-infected IRF8KO mice mounted a more robust anti-HSV-1 immune response, which included marked expansion of HSV-1-specific CD8+ T cells, increased infiltration of inflammatory cells into the cornea and trigeminal ganglia (TG) and enhanced elimination of virus within the trigeminal ganglion. However, the consequence of the enhanced immunological response was the development of ocular inflammation, limbitis, and neutrophilic infiltration into the cornea of HSV-1-infected IRF8KO mice. Surprisingly, we observed a marked increase in virus-specific memory precursor effector cells (MPEC) in IRF8KO mice, suggesting that IRF8 might play a role in regulating the differentiation of effector CD8+ T cells to the memory phenotype. Together, our data suggest that IRF8 might play a role in restraining excess lymphocyte proliferation. Thus, modulating IRF8 levels in T cells can be exploited therapeutically to prevent immune-mediated ocular pathology during autoimmune and infectious diseases of the eye. [ABSTRACT FROM AUTHOR]

Mice with targeted deletion of STAT3 in CD4+ T-cells do not develop experimental autoimmune uveitis (EAU) or experimental autoimmune encephalomyelitis (EAE), in part, because they cannot generate pathogenic Th17 cells. In this study, we have used ORLL-NIH001, a small synthetic compound that inhibits transcriptional activity of STAT3, to ameliorate EAU, an animal model of human posterior uveitis. We show that by attenuating inflammatory properties of uveitogenic lymphocytes, ORLL-NIH001 inhibited the recruitment of inflammatory cells into the retina during EAU and prevented the massive destruction of the neuroretina caused by pro-inflammatory cytokines produced by the autoreactive lymphocytes. Decrease in disease severity observed in ORLL-NIH001-treated mice, correlated with the down-regulation of α4β1 and α4β7 integrin activation and marked reduction of CCR6 and CXCR3 expression, providing a mechanism by which ORLL-NIH001 mitigated EAU. Furthermore, we show that ORLL-NIH001 inhibited the expansion of human Th17 cells, underscoring its potential as a drug for the treatment of human uveitis. Two synthetic molecules that target the Th17 lineage transcription factors, RORγt and RORα, have recently been suggested as potential drugs for inhibiting Th17 development and treating CNS inflammatory diseases. However, inhibiting STAT3 pathways completely blocks Th17 development, as well as, prevents trafficking of inflammatory cells into CNS tissues, making STAT3 a more attractive therapeutic target. Thus, use of ORLLNIH001 to target the STAT3 transcription factor, thereby antagonizing Th17 expansion and expression of proteins that mediate T cell chemotaxis, provides an attractive new therapeutic approach for treatment of posterior uveitis and other CNS autoimmune diseases mediated by Th17 cells. [ABSTRACT FROM AUTHOR]

T-helper type 17 cells (TH17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. TH17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-γ. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-α in retinal cells, suggesting a mechanism by which TH17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-γ and inhibited proliferation of TH17. These findings suggest that TH1 cells may mitigate uveitis by antagonizing the TH17 phenotype through the IFN-γ–mediated induction of IL-27 in target tissue. The finding that IL-2 promotes TH17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of TH17 by IFN-γ and/or IL-27 could be used for the treatment of chronic inflammation. [ABSTRACT FROM AUTHOR]

Suppressors of cytokine signaling (SOCS) have been implicated in regulation of T-cell activation and cytokine-mediated differentiation of T-helper cells. In this study we have characterized the pattern of SOCS expression in naive and activated primary T-helper cells, examined whether expression of SOCS genes is regulated by cytokine or T-cell receptor signaling, and analyzed the function of SOCS in differentiated T-cells. We show that SOCS1, SOCS2, SOCS3, CIS (cytokine-induced SH2 protein) genes are constitutively expressed in naive T-helper cells, with SOCS3 being the most abundant. Antigen stimulation of naive T-helper cells down-regulates SOCS3 expression and concomitantly up-regulates SOCS1, SOCS2, and CIS gene transcription, suggesting that SOCS genes are regulated differentially by T-cell activation. Down-regulation of SOCS3 expression is subsequently followed by gradual increase in SOCS3 level and corresponding decline in interleukin 2 (IL-2) secretion. In fact, SOCS3 mRNA levels are inversely correlated with the amount of IL-2 secretion and proliferative responses of differentiating T-helper cells, suggesting mutually antagonistic effects of SOCS3 and IL-2 and feedback regulation of T-cell activation by SOCS3. Furthermore, the degree of SOCS3 inhibition is antigen concentration-dependent and is mediated in part by growth factor independence-1, a T-cell transcription factor that regulates S-phase entry in T-cells. Forced overexpression of SOCS3 inhibits proliferation of T-helper cells, whereas depletion of endogenous SOCS3 by antisense SOCS3 cDNA enhances T-cell receptor- and cytokine-induced proliferation. Taken together, these results suggest a role for SOCS3 in maintaining T-helper cells in a quiescent state. Transient inhibition of SOCS3 by antigen stimulation may therefore be essential in allowing activation of resting T-cells. [ABSTRACT FROM AUTHOR]