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It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4(+) T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig-mediated TH17 suppression. Together, we propose the existence of a novel B7-H1-mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity., (Copyright © 2015 by The American Association of Immunologists, Inc.)

An important regulatory suppressive function in autoimmune and other inflammatory processes has been ascribed to CD4(+)Foxp3(+) regulatory T cells (Tregs), which requires direct cell-cell communication between Tregs, effector T cells, and APCs. However, the molecular basis for these interactions has not yet been clarified. We show here that sialoadhesin (Sn), the prototype of the siglec family of sialic acid-binding transmembrane proteins, expressed by resident and activated tissue-infiltrating macrophages, directly binds to Tregs, negatively regulating their expansion in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). In this model, macrophages infiltrate the CNS exhibiting tissue-destructing and demyelinating activity, leading to MS-like symptoms. We show here that severity of EAE symptoms is reduced in Sn knockout (KO) mice compared with wild-type littermates due to an up-regulation of CD4(+)Foxp3(+) Treg lymphocytes. Through the use of a Sn fusion protein, Tregs were shown to express substantial amounts of Sn ligand on their cell surface, and direct interaction of Sn(+) macrophages with Tregs specifically inhibited Treg but not effector T lymphocyte proliferation. Conversely, blocking of Sn on macrophages by Sn-specific Abs resulted in elevated proliferation of Tregs. Data indicate that Sn(+) macrophages regulate Treg homeostasis which subsequently influences EAE progression. We propose a new direct cell-cell interaction-based mechanism regulating the expansion of the Tregs during the immune response, representing a "dialogue" between Sn(+) macrophages and Sn-accessible sialic acid residues on Treg lymphocytes.

Galectins, a family of structurally related beta-galactoside-binding proteins, are expressed by various cells of the immune systems and seem to be important for the regulation of immune responses and immune cell homeostasis. Since it has been demonstrated that galectin-2 regulates cell-mediated inflammatory bowel disease and colitis in mice, we intended to investigate the role of galectin-2 in inflammatory cutaneous T cell-mediated immune responses. To address this issue, groups of naive mice were sensitized to the contact allergen 2,4-dinitro-1-fluorobenzene and systemically treated with galectin-2 to analyze the effects of galectin-2 on contact allergy. Here we show that galectin-2 is expressed in murine skin and is up-regulated upon cutaneous inflammation. Interestingly, treatment of mice with galectin-2 significantly reduced the contact allergy response. This effect was long-lasting since rechallenge of galectin-2-treated mice after a 14-day interval still resulted in a decreased ear swelling. We were able to demonstrate that galectin-2 induced a reduction of MHC class I-restricted immune responses in the treated animals, which was mediated by the induction of apoptosis specifically in activated CD8(+) T cells. Additionally, we report that the galectin-2-binding protein CD29 is up-regulated on the surface of activated CD8(+) T cells compared with naive CD8(+) T cells or CD4(+) T cells, suggesting that increased galectin-2/CD29 signaling might be responsible for the proapoptotic effects of galectin-2 on activated CD8(+) T cells. Taken together, these data indicate that galectin-2 may represent a novel therapeutic alternative for the treatment of CD8-mediated inflammatory disorders such as contact allergy.

UV radiation-induced immunosuppression contributes significantly to the development of UV-induced skin cancer by inhibiting protective immune responses. IL-10 has been shown to be a key mediator of UV-induced immunosuppression. To investigate the role of IL-10 during photocarcinogenesis, groups of IL-10(+/+), IL-10(+/-), and IL-10(-/-) mice were chronically irradiated with UV. IL-10(+/+) and IL-10(+/-) mice developed skin cancer to similar extents, whereas IL-10(-/-) mice were protected against the induction of skin malignancies by UV. Because UV is able to induce regulatory T cells, which play a role in the suppression of protective immunity, UV-induced regulatory T cell function was analyzed. Splenic regulatory T cells from UV-irradiated IL-10(-/-) mice were unable to confer immunosuppression upon transfer into naive recipients. UV-induced CD4+CD25+ T cells from IL-10(-/-) mice showed impaired suppressor function when cocultured with conventional CD4+CD25- T cells. CD4+CD25- T cells from IL-10(-/-) mice produced increased amounts of IFN-gamma and enhanced numbers of CD4+TIM-3+ T cells were detectable within UV-induced tumors in IL-10(-/-) mice, suggesting strong Th1-driven immunity. Mice treated with CD8+ T cells from UV-irradiated IL-10(-/-) mice rejected a UV tumor challenge significantly faster, and augmented numbers of granzyme A+ cells were detected within injected UV tumors in IL-10(-/-) animals, suggesting marked antitumoral CTL responses. Together, these findings indicate that IL-10 is critically involved in antitumoral immunity during photocarcinogenesis. Moreover, these results point out the crucial role of Th1 responses and UV-induced regulatory T cell function in the protection against UV-induced tumor development.

Foxp3 functions as a lineage specification factor for the development of naturally occurring thymus-derived CD4+CD25+ regulatory T (Treg) cells. Recent evidence suggests that naive Foxp3-CD4+CD25- T cells can be converted in the periphery into Foxp3+ Treg cells. In this study, we have identified the G protein-coupled receptor (GPR)83 to be selectively up-regulated by CD4+CD25+ Treg cells of both murine and human origin in contrast to naive CD4+CD25- or recently activated T cells. Furthermore, GPR83 was induced upon overexpression of Foxp3 in naive CD4+CD25- T cells. Transduction of naive CD4+CD25- T cells with GPR83-encoding retroviruses did not confer in vitro suppressive activity. Nevertheless, GPR83-transduced T cells were able to inhibit the effector phase of a severe contact hypersensitivity reaction of the skin, indicating that GPR83 itself or GPR83-mediated signals conferred suppressive activity to conventional CD4+ T cells in vivo. Most strikingly, this in vivo acquisition of suppressive activity was associated with the induction of Foxp3 expression in GPR83-transduced CD4+ T cells under inflammatory conditions. Our results suggest that GPR83 might be critically involved in the peripheral generation of Foxp3+ Treg cells in vivo.

Epicutaneous application of dinitrothiocyanobenzene (DNTB) induces tolerance against its related compound dinitrofluorobenzene (DNFB), because DNTB-pretreated mice cannot be sensitized against the potent hapten DNFB. This tolerance is hapten-specific and transferable. In this study, we demonstrate that IL-12 can break DNTB-mediated tolerance. Furthermore, naive mice treated with IL-12 before DNTB application responded to DNFB challenge with a pronounced ear swelling response without previous sensitization to DNFB, showing that IL-12 can convert the tolerogen DNTB into an immunogen. No differences in numbers or regulatory activity were observed between CD4+CD25+ regulatory T cells isolated from mice treated with DNFB, DNTB, or IL-12 followed by DNTB. However, the number of CD207+ Langerhans cells in regional lymph nodes of DNTB-treated mice was significantly lower than in animals treated with DNFB or IL-12 plus DNTB. Additionally, CD11c+ dendritic cells (DC) isolated from regional lymph nodes of DNTB-treated mice had a significantly lower ability to stimulate T cell proliferation and produced reduced amounts of inflammatory cytokines. Application of both DNFB and DNTB induced apoptotic cell death of DC in the epidermis and the regional lymph nodes. However, the number of apoptotic DC in regional lymph nodes was significantly higher in DNTB-treated animals compared with mice treated with DNFB or IL-12 plus DNTB. Therefore, we conclude that DNTB-mediated tolerance is secondary to inefficient Ag presentation as a result of apoptotic cell death of DC and that IL-12 converts the tolerogen DNTB into an immunogen by preventing DNTB-induced apoptosis of DC.

Although previous studies have shown that altered B7 costimulation plays a critical role in UV irradiation-induced regulation of immunity, the individual roles of the B7 receptors (CD28 and CTLA-4) or the B7 family members (CD80 and CD86) have not been explored. Thus, we investigated CTLA-4 signaling during photocarcinogenesis of chronically UV-B-exposed mice using an antagonistic anti-CTLA-4 Ab. Anti-CTLA-4-treated mice developed significantly fewer UV-induced tumors. Moreover, anti-CTLA-4 treatment induced long-lasting protective immunity because progressively growing UV tumors inoculated into anti-CTLA-4- and UV-treated mice that had not developed tumors were rejected. Next, we used mice deficient for CD80, CD86, or both in photocarcinogenesis studies to assess the relative contributions of these CTLA-4 ligands. Double-deficient mice showed significantly reduced UV-induced skin tumor development, whereas CD86(-/-) mice produced skin cancer earlier compared with CD80(-/-) and control mice. The growth of UV-induced tumors appears to be controlled by UV-induced suppressor T cells, because CD80(-/-)/CD86(-/-) mice had strongly reduced numbers of UV-induced CD4(+)CD25(+) suppressor T cells. In vitro, CTLA-4 blockade inhibited the suppressor activity of UV-induced CD4(+)CD25(+) T cells, suggesting that reduced photocarcinogenesis might be due to decreased numbers or function of suppressor T cells. Together, these data indicate that blocking CD80/86-CTLA-4 signaling induced immune protection against the development of UV-induced skin tumors. Furthermore, CD86-mediated costimulation appears to play a more critical role in the protection against photocarcinogenesis than CD80.

In a CD18 hypomorphic polygenic PL/J mouse model, the severe reduction of CD18 (beta(2) integrin) to 2-16% of wild-type levels leads to the development of a psoriasiform skin disease. In this study, we analyzed the influence of reduced CD18 gene expression on T cell function, and its contribution to the pathogenesis of this disease. Both CD4(+) and CD8(+) T cells were significantly increased in the skin of affected CD18 hypomorphic mice. But only depletion of CD4(+) T cells, and not the removal of CD8(+) T cells, resulted in a complete clearance of the psoriasiform dermatitis. This indicates a central role of CD4(+) T cells in the pathogenesis of this disorder, further supported by the detection of several Th1-like cytokines released predominantly by CD4(+) T cells. In contrast to the CD18 hypomorphic mice, CD18 null mutants of the same strain did not develop the psoriasiform dermatitis. This is in part due to a lack of T cell emigration from dermal blood vessels, as experimental allergic contact dermatitis could be induced in CD18 hypomorphic and wild-type mice, but not in CD18 null mutants. Hence, 2-16% of CD18 gene expression is obviously sufficient for T cell emigration driving the inflammatory phenotype in CD18 hypomorphic mice. Our data suggest that the pathogenic involvement of CD4(+) T cells depends on a gene dose effect with a reduced expression of the CD18 protein in PL/J mice. This murine inflammatory skin model may also have relevance for human polygenic inflammatory diseases.