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Background: IL-9 is a growth factor for T- and mast-cells that is secreted by human Th2 cells. We recently reported that IL- 4+TGF-β directs mouse CD4+CD25-CD62L+ T cells to commit to inflammatory IL-9 producing CD4+ T cells. Methodology/Principal Findings: Here we show that human inducible regulatory T cells (iTregs) also express IL-9. IL-4+TGF-β induced higher levels of IL-9 expression in plate bound-anti-CD3 mAb (pbCD3)/soluble-anti-CD28 mAb (sCD28) activated human resting memory CD4+CD25-CD45RO+ T cells as compared to naïve CD4+CD25-CD45RA+ T cells. In addition, as compared to pbCD3/sCD28 plus TGF-β stimulation, IL-4+TGF-β stimulated memory CD4+CD25-CD45RO+ T cells expressed reduced FOXP3 protein. As analyzed by pre-amplification boosted single-cell real-time PCR, human CD4+IL-9+ T cells expressed GATA3 and RORC, but not IL-10, IL-13, IFNγ or IL-17A/F. Attempts to optimize IL-9 production by pbCD3/sCD28 and IL-4+TGF-β stimulated resting memory CD4+ T cells demonstrated that the addition of IL-1β, IL-12, and IL-21 further enhance IL-9 production. Conclusions/Significance: Taken together these data show both the differences and similarities between mouse and human CD4+IL9+ T cells and reaffirm the powerful influence of inflammatory cytokines to shape the response of activated CD4+ T cells to antigen. [ABSTRACT FROM AUTHOR]

In short, manipulation of cytokine pathways shows promise as a mean to tilt the balance of immunity toward tolerance. Effective and regulatory T cells vary in their response to a variety of cytokines. In particular, the ability of certain cytokines, for example, IL-2, to provide vital survival signals to regulatory cells and to trigger death of effector T cells or impede IL-15 driven expansion of memory cells has spurred several trials. The ability of IFNγ, IL-4, TNFα, and lymphotoxin to exert selective effects upon crucial lymphocyte subset populations in vivo may also enable translation into potent therapies. [Copyright &y& Elsevier]

T-cell immunoglobulin mucin-3 (TIM-3) is only expressed by differentiated TH1 cells following their proliferative response to antigen, functioning to terminate TH1-mediated immunity upon binding to the TIM-3 ligand, galectin-9. This critical regulatory process involves Treg cells via their stable expression of galectin-9. Soluble TIM-3-Ig blocks galectin-9 and prevents induction of peripheral tolerance. Here we have looked for evidence that TIM-3-Ig might also break established regulatory tolerance. Using allo-primed spleen cells cultured ex vivo and challenged with irradiated donor-type stimulator cells either alone or together with 20 μg/ml TIM-3-Ig, we measured daily cytokine release [IL2, inferon gamma (INFγ), transforming growth factor beta (TGFβ), IL6, IL10] and cellular Foxp3 protein. In allo-tolerance, a specific effect of TIM-3-Ig was some fourfold reduction in TGFβ. Foxp3 was induced in the allo-tolerant response to donor and this was not altered by TIM-3-Ig over the 5-day culture period. No Foxp3 was detected in either rejected or donor stimulator cells at any time. Thus, in an ex vivo model of in vivo tolerance to heart allografts, TIM-3-Ig therapy appears to reduce the stable tolerogenic environment by a rapid and specific repression of TGFβ release. [ABSTRACT FROM AUTHOR]

On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (TH)1 and TH2 cells, producing interleukin (IL)-17 (TH17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-β and IL-6 together induce the differentiation of TH17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (Treg cells) or TH17 cells. Whereas TGF-β induces Foxp3 and generates Treg cells, IL-6 inhibits the generation of Treg cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for TH17 and Treg cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a TH17 response and their peripheral repertoire is dominated by Foxp3+ Treg cells. However, deletion of Treg cells leads to the reappearance of TH17 cells in Il6-/- mice, suggesting an additional pathway by which TH17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-β to induce TH17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a TH17 response. [ABSTRACT FROM AUTHOR]

The alloimmune response can be divided into specific junctures where critical decisions between tolerance and immunity are made which define the outcome of the transplant. At these “decision nodes” various cytokines direct alloresponsive T cells to develop either a proinflammatory response aimed at graft destruction or an immunoregulatory response facilitating graft acceptance. This review will focus on the role of these cytokines in influencing the progression of an alloimmune response leading ultimately to either allograft survival or rejection. [Copyright &y& Elsevier]

T helper type 1 (TH1) immune responses are central in cell-mediated immunity, and a TH1-specific cell surface molecule called Tim-3 (T cell immunoglobulin domain, mucin domain) has been identified. Here we report the identification of a secreted form of Tim-3 that contains only the immunoglobulin (Ig) variable (V) domain of the full-length molecule. Fusion proteins (Tim-3-Ig) of both Tim-3 isoforms specifically bound CD4+ T cells, indicating that a Tim-3 ligand is expressed on CD4+ T cells. Administration of Tim-3-Ig to immunized mice caused hyperproliferation of TH1 cells and TH1 cytokine release. Tim-3-Ig also abrogated tolerance induction in TH1 cells, and Tim-3-deficient mice were refractory to the induction of high-dose tolerance. These data indicate that interaction of Tim-3 with Tim-3 ligand may serve to inhibit effector TH1 cells during a normal immune response and may be crucial for the induction of peripheral tolerance. [ABSTRACT FROM AUTHOR]

Early murine fetal thymocytes express functional, high affinity IL-2 receptors as determined by: (i) the presence of IL-2R β chain (p75) mRNA; (II) IL-2 (10 U/ml) induced cell proliferation/cellular maturation in lobe submersion cultures (LSC). Under the Influence of IL-2, early thymocytes differentiate into more mature, early single positive CD4CD8 followed by double positive CDCD8 and single positive CD4CD8T and CD4CD8 thymocytes. Specific intoxication of high affinity IL-2R positive thymocytes by recombinant interleukin-2-diphtheria toxin-related fusion protein (DAB-IL-2) results In transent, dose dependent blockade of and thymocyte maturation. DAB-IL-2 induced effects upon maturation are reversible within 2 weeks after cessation of drug administration. Taken together, these results demonstrate the expression of functional, high affinity IL-2 receptors on early thymocytes. Elimination of high affinity IL-2 receptor positive thymocytes with DAB-IL-2 results in transient blockade of T cell maturation. Since DAB-IL-2 is now in clinical trial, it is reassuring to note that it does not permanently disrupt thymic maturation. [ABSTRACT FROM PUBLISHER]

Transplantation of organs between genetically different individuals of the same species causes a T cell–mediated immune response that, if left unchecked, results in rejection and graft destruction. The potency of the alloimmune response is determined by the antigenic disparity that usually exists between donors and recipients and by intragraft expression of proinflammatory cytokines in the early period after transplantation. Studies in animal models have identified many molecules that, when targeted, inhibit T-cell activation. In addition, some of these studies have shown that certain immunologic interventions induce transplantation tolerance, a state in which the allograft is specifically accepted without the need for chronic immunosuppression. Tolerance is an important aspect of liver transplantation, because livers have a unique microenvironment that promotes tolerance rather than immunity. In contrast to the progress achieved in inducing tolerance in animal models, patients who receive transplanted organs still require nonspecific immunosuppressant drugs. The development of calcineurin inhibitors has reduced the acute rejection rate and improved short-term, but not long-term, graft survival. However, long-term use of immunosuppressive drugs leads to nephrotoxicity and metabolic disorders, as well as manifestations of overimmunosuppression such as opportunistic infections and cancers. The status of pharmacologic immunosuppression in the clinic is therefore not ideal. We review recently developed therapeutic strategies to promote tolerance to transplanted livers and other organs and diagnostic tools that might be used to identify patients most likely to accept or reject allografts. [Copyright &y& Elsevier]

T-cell immunoglobulin mucin-3 (Tim-3) is expressed on pathogenic T cells, and its ligand galectin-9 (gal-9) is up-regulated in inflamed tissues. When Tim-3+ T cells encounter high gal-9 levels, they are de-leted. Tim-3 is up-regulated on activated T cells during GVHD. Inhibition of Tim-3/ gal-9 binding by infusion of a Tim-3-lg fusion protein or Tim-3-/- donor T cells increased T-cell proliferation and GVHD lethality. When the Tim-3/gal-9 pathway engagement was augmented using gal-9 transgenic recipients, GVHD lethality was slowed. Together, these data indicate a potential for modulating this pathway to reduce disease by increasing Tim-3 or gal-9 engagement. Paradoxically, when Tim-3/gal-9 was inhibited in the absence of donor T-regulatory cells (Tregs), GVHD was inhibited. GVHD reduction was asso-ciated with decreased colonic inflamma-tory cytokines as well as epithelial barrier destruction. CD25-depleted Tim-3-/- donor T cells underwent increased activation-induced cell death because of increased IFN-γ production. To our knowledge, these studies are the first to show that although the absence of Tim-3/gal-9 pathway interac-tions augments systemic GVHD, concurrent donor Treg depletion paradoxically and sur-prisingly inhibits GVHD. Thus, although do-nor Tregs typically inhibit GVHD, under some conditions, such Tregs actually may contrib-ute to GVHD by reducing activation-induced T-cell death. {Blood. 2012;120(3):682-690). [ABSTRACT FROM AUTHOR]

The Th1 cytokines IL-2 and IFN-gamma, which inhibit T cell proliferation and promote activation induced cell death, may be required to diminish alloreactive T cell numbers and to foster tolerance across full allogeneic barriers. However, we hypothesized that these cytokines might be dispensable when the alloreactive T cell clone size is relatively small, as is seen in recipients of minor-mismatched grafts. We show that alloreactive T cell clone size of C57BL/6 mice against multiple minor-mismatched 129X1/sv mice was approximately 4-9-fold smaller than that against MHC-mismatched BALB/c mice. In the MHC-mismatched combination, CD28-B7 blockade by CTLA4Ig induced long-term graft survival in wild-type recipients, but this treatment was ineffective in IFNgamma(-/-) or IL-2(-/-) recipients. In contrast, in the minor-mismatched combination, CTLA4Ig induced long-term allograft survival in wild-type, IFNgamma(-/-), and IL-2(-/-) recipients. Bcl-x(L) transgenic animals, which are defective in "passive" T cell death, are likewise sensitive to the effects of CTLA4Ig only in the setting of the minor-mismatch grafts. Therefore, the alloreactive T cell clone size is an important determinant affecting the need for Th1 cytokines and T cell death in tolerance induction. These data have implications for the design of tolerance strategies in transplant recipients with varying degrees of MHC mismatching. [ABSTRACT FROM AUTHOR]