IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells.

Transcription factor Foxp3 is critical for generating regulatory T cells (T(reg) cells). Transforming growth factor-beta (TGF-beta) induces Foxp3 and suppressive T(reg) cells from naive T cells, whereas interleukin 6 (IL-6) inhibits the generation of inducible T(reg) cells. Here we show that IL-4 blocked the generation of TGF-beta-induced Foxp3(+) T(reg) cells and instead induced a population of T helper cells that produced IL-9 and IL-10. The IL-9(+)IL-10(+) T cells demonstrated no regulatory properties despite producing abundant IL-10. Adoptive transfer of IL-9(+)IL-10(+) T cells into recombination-activating gene 1-deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9(+)IL-10(+) T cells were transferred with CD45RB(hi) CD4(+) effector T cells. Thus IL-9(+)IL-10(+) T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.

Alpha-1 antitrypsin treatment of new-onset type 1 diabetes: An open-label, phase I clinical trial (RETAIN) to assess safety and pharmacokinetics.

OBJECTIVE: To determine the safety and pharmacokinetics of alpha-1 antitrypsin (AAT) in adults and children. RESEARCH DESIGN AND METHODS: Short-term AAT treatment restores euglycemia in the non-obese mouse model of type 1 diabetes. A phase I multicenter study in 16 subjects with new-onset type 1 diabetes studied the safety and pharmacokinetics of Aralast NP (AAT). This open-label, dose-escalation study enrolled 8 adults aged 16 to 35 years and 8 children aged 8 to 15 years within 100 days of diagnosis, to receive 12 infusions of AAT: a low dose of 45 mg/kg weekly for 6 weeks, followed by a higher dose of 90 mg/kg for 6 weeks. RESULTS: C-peptide secretion during a mixed meal, hemoglobin A1c (HbA1c), and insulin usage remained relatively stable during the treatment period. At 72 hours after infusion of 90 mg/kg, mean levels of AAT fell below 2.0 g/L for 7 of 15 subjects. To identify a plasma level of AAT likely to be therapeutic, pharmacodynamic ex vivo assays were performed on fresh whole blood from adult subjects. Polymerase chain reaction (PCR) analyses were performed on inhibitor of IKBKE, NOD1, TLR1, and TRAD gene expression, which are important for activation of nuclear factor-κB (NF-κB) and apoptosis pathways. AAT suppressed expression dose-dependently; 50% inhibition was achieved in the 2.5 to 5.0 mg/mL range. CONCLUSIONS: AAT was well tolerated and safe in subjects with new-onset type 1 diabetes. Weekly doses of AAT greater than 90 mg/kg may be necessary for an optimal therapeutic effect.

In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche.

Stem cells reside in a specialized regulatory microenvironment or niche, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity. The niche may also protect stem cells from environmental insults including cytotoxic chemotherapy and perhaps pathogenic immunity. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression. We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche in the bone marrow, a site where immune reactivity exists. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T(reg)) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with T(reg) cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T(reg) cells seem to participate in creating a localized zone where HSPCs reside and where T(reg) cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.

Leptin deficiency impairs maturation of dendritic cells and enhances induction of regulatory T and Th17 cells.

Leptin is an adipose-secreted hormone that plays an important role in both metabolism and immunity. Leptin has been shown to induce Th1-cell polarization and inhibit Th2-cell responses. Additionally, leptin induces Th17-cell responses, inhibits regulatory T (Treg) cells and modulates autoimmune diseases. Here, we investigated whether leptin mediates its activity on T cells by influencing dendritic cells (DCs) to promote Th17 and Treg-cell immune responses in mice. We observed that leptin deficiency (i) reduced the expression of DC maturation markers, (ii) decreased DC production of IL-12, TNF-α, and IL-6, (iii) increased DC production of TGF-ß, and (iv) limited the capacity of DCs to induce syngeneic CD4(+) T-cell proliferation. As a consequence of this unique phenotype, DCs generated under leptin-free conditions induced Treg or TH 17 cells more efficiently than DCs generated in the presence of leptin. These data indicate important roles for leptin in DC homeostasis and the initiation and maintenance of inflammatory and regulatory immune responses by DCs.

Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival.

The promise of islet cell transplantation cannot be fully realized in the absence of improvements in engraftment of resilient islets. The marginal mass of islets surviving the serial peritransplant insults may lead to exhaustion and thereby contribute to an unacceptably high rate of intermediate and long-term graft loss. Hence, we have studied the effects of treatment with alpha 1-antitrypsin (AAT) in a syngeneic nonautoimmune islet graft model. A marginal number of syngeneic mouse islets were transplanted into nonautoimmune diabetic hosts and islet function was analyzed in control and AAT treated hosts. In untreated controls, marginal mass islet transplants did not restore euglycemia. Outcomes were dramatically improved by short-term AAT treatment. Transcriptional profiling identified 1,184 differentially expressed transcripts in AAT-treated hosts at 3 d posttransplantation. Systems-biology-based analysis revealed AAT down-regulated regulatory hubs formed by inflammation-related molecules (e.g., TNF-α, NF-κB). The conclusions yielded by the systems-biology analysis were rigorously confirmed by QRT-PCR and immunohistology. These data suggest that short-term AAT treatment of human islet transplant recipients may be worthy of a clinical trial.

Innate immunity for better or worse govern the allograft response.

PURPOSE OF REVIEW: To update knowledge concerning the cause and consequences of the detrimental forms of innate immunity that inevitably occurs in peritransplant period tissue and cellular transplants. In addition, we review the information that a newly discovered, engraftment-promoting, and tolerance-inducing macrophage population is identified and characterized. RECENT FINDINGS: The allograft response mounted by adaptive immune cells is shaped by innate immunity. The early allograft response is uniquely intense as a result of activation of the innate immune response created by ischemia reperfusion injury in organ transplants, delayed revascularization of cell transplants, and hypoxia. Inflammation is created by both cellular 'debris' and cytokines. However, a newly discovered prominent, albeit fragile, tissue-resident, noninvasive, and immunoregulatory macrophage promotes engraftment and tolerance. The role of intracellular 'debris' as well as inflammation in evoking detrimental rejection-provoking peritransplant inflammation is emphasized as well as characterization of a prominent and highly immunoregulatory albeit fragile macrophage population that is tissue-resident and does not circulate is characterized. SUMMARY: Opportunity lies in the ability to rein in detrimental peri-transplant inflammation and in the ability to promote the longevity of a subpopulation of highly potent tissue-resident immunoregulatory macrophages.

Role of myeloid-derived suppressor cells in mouse pre-sensitized cardiac transplant model.

Harness of sensitized transplantation remains a clinical challenge particularly in parallel with prolonged cold ischemia time (PCI)-mediated injury. Our present study was to test the role of myeloid-derived suppressor cells (MDSCs) in mouse pre-sensitized transplantation. Our findings revealed that CD11b+Gr1(low) MDSC was shown to have strong suppressive activity. MDSCs subsets from the tolerated mice exhibited higher suppressive capacities compared with counterparts from naive (untreated) mice. Depletion of Tregs could not affect splenic CD11b+Gr1(-low) MDSC frequency, but increase peripheral and intragraft CD11b+Gr1(-low) frequency. Intriguingly, boost of Tregs remarkably caused an increase of CD11b+Gr1(-low) frequency in the graft, peripheral blood, and spleen. Furthermore, peripheral CD11b+Gr1(-low) cells were massively accumulated at the early stage when allogeneic immune response was enhanced. Taken together, MDSCs could prevent grafts from PCI-mediated injury independent on Tregs in the pre-sensitized transplant recipients. Utilization of MDSC subset particularly CD11b+Gr1(-low) might provide a novel insight into improving graft outcome under such clinical scenarios.

Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells.

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 deleted. Tim-3 is up-regulated on activated T cells during GVHD. Inhibition of Tim-3/gal-9 binding by infusion of a Tim-3-Ig 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 associated with decreased colonic inflammatory 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 interactions augments systemic GVHD, concurrent donor Treg depletion paradoxically and surprisingly inhibits GVHD. Thus, although donor Tregs typically inhibit GVHD, under some conditions, such Tregs actually may contribute to GVHD by reducing activation-induced T-cell death.

Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation.

Treatment with ex vivo-generated regulatory T cells (T-reg) has been regarded as a potentially attractive therapeutic approach for autoimmune diseases. However, the dynamics and function of T-reg in autoimmunity are not well understood. Thus, we developed Foxp3gfp knock-in (Foxp3gfp.KI) mice and myelin oligodendrocyte glycoprotein (MOG)(35-55)/IA(b) (MHC class II) tetramers to track autoantigen-specific effector T cells (T-eff) and T-reg in vivo during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. MOG tetramer-reactive, Foxp3(+) T-reg expanded in the peripheral lymphoid compartment and readily accumulated in the central nervous system (CNS), but did not prevent the onset of disease. Foxp3(+) T cells isolated from the CNS were effective in suppressing naive MOG-specific T cells, but failed to control CNS-derived encephalitogenic T-eff that secreted interleukin (IL)-6 and tumor necrosis factor (TNF). Our data suggest that in order for CD4(+)Foxp3(+) T-reg to effectively control autoimmune reactions in the target organ, it may also be necessary to control tissue inflammation.

A20--a biomarker of allograft outcome: a showcase in kidney transplantation.

Effective means to identify anti-donor immune activity before the transplant organ is damaged and rejected has been an important goal in transplantation research. Development of sensitive and non-invasive diagnostic methods that probe the immune status of the recipient as well as the resilience of the donor organ should enable personalized application of immunosuppressive drugs. With a non-invasive biomarker for rejection, it should be possible to selectively treat the patients that are rejecting the graft and wean the tolerant patients from immunosuppression. Although A20 is also expressed by activated CD4+ T cells and CD8+ T cells, its expression by mouse tubular cells has been shown to play an important role in protecting allografts from ischemia/reperfusion (I/R) injury and rejection. Using quantitative (real-time) reverse transcriptase polymerase chain reaction (qt-RT-PCR), we showed that expression levels of A20, heme oxygenase (HO)-1, other anti-apoptotic molecules, granzyme-B (GZMB), perforin (PRF1), CD3 and other immune molecules in renal transplant biopsies, urinary cells and peripheral blood cells are predictive of transplantation outcomes. Measuring A20 at mRNA and protein levels has the potentiality to be diagnostic and prognostic of transplantation outcomes and thereby help in timely therapeutic interventions to prolong graft life.

Hand transplants and the mandate for tolerance.

PURPOSE OF REVIEW: The field of vascularized composite allograft (VCA) to achieve its full potential will require induction of tolerance. This review will introduce a new method of potential inducing tolerance in hand transplantation. RECENT FINDINGS: Hand transplantation is never a life-extending transplant. This fact resulted in considerable debate both for and against the use of immunosuppression for nonlife-extending transplants. There is considerable debate about the ethics of hand transplantation. There is now consensus that nonlife-extending transplants are acceptable in properly selected patients. However, ideally, hand transplants should not receive life-long immunosuppression. Therefore, attempts to achieve drug-free tolerance through nonlife-endangering therapies are warranted. To this end, we propose implementation of tolerizing therapy long after periinflammation has subsided and drug minimization has proven successful. Evidence that short-term treatment with low doses of IL-2 or a long-lived IL-2 immunoglobulin (Ig) can tilt the balance of immunity from tissue destructive to tolerance come from preclinical demonstrations in mouse and nonhuman primate models of autoimmunity and/or transplantation and even more recent clinical trials. SUMMARY: We believe that with the proper use of low-dose IL-2 given at an opportune time in the inflammatory process of transplant that reduce immunosuppression and even tolerance can be induced in hand transplantation. We propose that tolerance can be inducted after a long period of conventional treatment to avoid 'tolerance-hindering' adverse inflammation that occurs in the posttransplant period. With abatement of posttransplant inflammation and with time, we will institute low-dose IL-2-based therapy to support the proliferation, viability and functional phenotype of regulatory T cells.

Acute rejection in vascularized composite allotransplantation.

PURPOSE OF REVIEW: Acute rejection is the most common complication after vascularized composite allotransplantation (VCA). This review provides a state-of-the-art analysis of prevention, diagnosis and treatment of acute rejection episodes and highlights recent findings with the potential to improve patient care and enhance understanding of the underlying biologic processes. RECENT FINDINGS: Recent reports suggest that maintenance immunosuppression dose reduction and steroid withdrawal are realistic goals in VCA, despite the known high immunogenicity of the skin component. It appears that utilization of sentinel flaps, in-depth histological analyses and application of novel biomarkers have facilitated early diagnosis and characterization of acute rejection episodes, leading to timely institution of appropriate therapy. The successful management of the first highly sensitized face transplant recipient suggests the possibility of carefully considering these high-risk VCA candidates for transplantation. SUMMARY: Acute rejection is higher in VCA than in any other organ in the field of transplantation, although most episodes are controlled by high-dose steroids and optimization of maintenance immunosuppression. Because of limitations in patient number and the duration of follow-up, the long-term safety and effectiveness of VCA remain unclear. Moreover, the tests currently used to diagnose acute rejection are of limited value. Better diagnostic tools and a better understanding of the immunologic events during acute rejection are therefore needed to improve diagnosis, treatment and outcomes of this life-changing restorative surgery.

Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.

The study of T regulatory cells (T reg cells) has been limited by the lack of specific surface markers and an inability to define mechanisms of suppression. We show that the expression of CD39/ENTPD1 in concert with CD73/ecto-5'-nucleotidase distinguishes CD4(+)/CD25(+)/Foxp3(+) T reg cells from other T cells. These ectoenzymes generate pericellular adenosine from extracellular nucleotides. The coordinated expression of CD39/CD73 on T reg cells and the adenosine A2A receptor on activated T effector cells generates immunosuppressive loops, indicating roles in the inhibitory function of T reg cells. Consequently, T reg cells from Cd39-null mice show impaired suppressive properties in vitro and fail to block allograft rejection in vivo. We conclude that CD39 and CD73 are surface markers of T reg cells that impart a specific biochemical signature characterized by adenosine generation that has functional relevance for cellular immunoregulation.

Molecular characterization and functional activity of an IL-15 antagonist MutIL-15/Fc human fusion protein.

Fc fusion proteins are a new emerging class of molecules for immune-targeted delivery of therapeutic proteins. Biophysical and bioanalytical characterization is critical for clinical development and delivery of therapeutic proteins. Here we report molecular and functional characterization of a recombinant human fusion protein Mutant IL-15/Fc. MutIL-15/Fc has a molecular weight of ∼95 kDa as determined by multiangle laser light scattering with online size exclusion chromatography and migrated at a faster rate (lower retention time) in gel filtration column. The kinetics of binding of MutIL-15/Fc to Fcγ receptor is best fitted in a bivalent modal with K(D1) 5 µM and K(D2) 9 µM determined by surface plasmon resonance (BIAcore). N-Glycoprofiling analysis revealed extensive glycosylation of MutIL-15/Fc. The Fc and IL-15 components in the MutIL-15/Fc are detected using the dual mode ELISA. The HT-2 cell proliferation inhibition assay is qualified as a quantitative in vitro marker functional assay. Molecular state changes associated with forced stress analyzed by SEC-MALS resulted in changes in bioactivity and Fc:Fcγ receptor interaction affinity. These data provide a systematic approach to molecular and functional characterization of the MutIL-15/Fc to establish product consistency and stability monitoring during storage and under drug delivery conditions.

IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells.

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 (T(H))1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) 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)-beta and IL-6 together induce the differentiation of T(H)17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (T(reg) cells) or T(H)17 cells. Whereas TGF-beta induces Foxp3 and generates T(reg) cells, IL-6 inhibits the generation of T(reg) cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T(H)17 and T(reg) cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3+ T(reg) cells. However, deletion of T(reg) cells leads to the reappearance of T(H)17 cells in Il6-/- mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response.

Orphan nuclear receptor Nur77 promotes acute kidney injury and renal epithelial apoptosis.

Nur77 and its family members Nurr1 and Nor-1 are inducible orphan nuclear receptors that orchestrate cellular responses to diverse extracellular signals. In epithelia, Nur77 can act as a potent proapoptotic molecule in response to cellular stress, suggesting a possible role for this nuclear receptor in the tissue response to injury. Here, we found that Nur77 promotes epithelial cell apoptosis after AKI. Injury of proximal tubular epithelial cells rapidly and strongly induced Nur77, Nor-1, and Nurr1 both in vitro and in vivo. After renal ischemia-reperfusion, Nurr77-deficient mice exhibited less apoptosis of tubular epithelial cells and better renal function than wild-type mice. Nur77-mediated renal injury involved a conformational change of Bcl2 and an increase in the protein levels of proapoptotic Bcl-xS. Ligand-activated retinoic acid receptors repressed Nur77 induction and function. Pretreatment of wild-type mice with retinoic acid before renal ischemia-reperfusion blunted the induction of Nur77, conferred protection of renal function, attenuated renal histologic injury, and reduced the expression of epithelial-derived proinflammatory cytokines. Retinoic acid also inhibited hypoxia-mediated induction of proinflammatory cytokines in cultured renal epithelial cells. Results obtained from proximal tubule cultures derived from Nur77-deficient mice suggested that the inhibition of Nur77 expression mediated the renoprotective effects of retinoic acid. In summary, Nur77 promotes epithelial apoptosis after ischemia-reperfusion injury, and retinoic acid-mediated inhibition of Nur77 expression is a promising therapeutic strategy for the prevention of AKI.

Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs.

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.

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T(H)) cells are traditionally thought to differentiate into T(H)1 and T(H)2 cell subsets. T(H)1 cells are necessary to clear intracellular pathogens and T(H)2 cells are important for clearing extracellular organisms. Recently, a subset of interleukin (IL)-17-producing T (T(H)17) cells distinct from T(H)1 or T(H)2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury. In contrast, CD4+CD25+Foxp3+ regulatory T (T(reg)) cells inhibit autoimmunity and protect against tissue injury. Transforming growth factor-beta (TGF-beta) is a critical differentiation factor for the generation of T(reg) cells. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation, completely inhibits the generation of Foxp3+ T(reg) cells induced by TGF-beta. We also demonstrate that IL-23 is not the differentiation factor for the generation of T(H)17 cells. Instead, IL-6 and TGF-beta together induce the differentiation of pathogenic T(H)17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T(H)17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

Mast cells are essential intermediaries in regulatory T-cell tolerance.

Contrary to the proinflammatory role of mast cells in allergic disorders, the results obtained in this study establish that mast cells are essential in CD4+CD25+Foxp3+ regulatory T (T(Reg))-cell-dependent peripheral tolerance. Here we confirm that tolerant allografts, which are sustained owing to the immunosuppressive effects of T(Reg) cells, acquire a unique genetic signature dominated by the expression of mast-cell-gene products. We also show that mast cells are crucial for allograft tolerance, through the inability to induce tolerance in mast-cell-deficient mice. High levels of interleukin (IL)-9--a mast cell growth and activation factor--are produced by activated T(Reg) cells, and IL-9 production seems important in mast cell recruitment to, and activation in, tolerant tissue. Our data indicate that IL-9 represents the functional link through which activated T(Reg) cells recruit and activate mast cells to mediate regional immune suppression, because neutralization of IL-9 greatly accelerates allograft rejection in tolerant mice. Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T(Reg)-IL-9-mast cell relationship within tolerant allografts.

Tim-2 regulates T helper type 2 responses and autoimmunity.

Identification of the T cell immunoglobulin mucin-domain containing (Tim) gene family introduced a new family of cell surface molecules that is involved in the regulation of immune responses. We previously demonstrated that Tim-3 is expressed on terminally differentiated T helper (Th)1 cells, and serves to regulate Th1 immune responses. Here, we describe the identification and function of Tim-2, a novel member of the Tim gene family. In contrast with Tim-3, we demonstrate that Tim-2 is expressed preferentially in differentiated Th2 cells. Blockade of the Tim-2/Tim-2 ligand interaction, by administration of soluble Tim-2 fusion protein (Tim-2 immunoglobulin [Ig]), results in T cell hyperproliferation and the production of Th2 cytokines. Administration of Tim-2 Ig during the induction phase reduces the severity of experimental autoimmune encephalomyelitis, a Th1-mediated autoimmune disease model of multiple sclerosis. We propose that Tim-2, an orthologue of human Tim-1, is critical for the regulation of Th2 responses during autoimmune inflammation.