Regulatory T cells: tolerance induction in solid organ transplantation

The concept of regulatory T cell (T_reg) therapy in transplantation is now a reality. Significant advances in science and technology have enabled us to isolate human T_regs, expand them to clinically relevant numbers and infuse them into human transplant recipients. With several Phase I/II trials under way investigating T_reg safety and efficacy it is now more crucial than ever to understand their complex biology. However, our journey is by no means complete; results from these trials will undoubtedly provoke both further knowledge and enquiry which, alongside evolving science, will continue to drive the optimization of T_reg therapy in the pursuit of transplantation tolerance. In this review we will summarize current knowledge of T_reg biology, explore novel technologies in the setting of T_reg immunotherapy and address key prerequisites surrounding the clinical application of T_regs in transplantation.     

Regulatory T cells in transplantation

Our ability to harness tolerance mechanisms will have a major impact in organ transplantation. It should enable drug minimization, and eventually, the elimination of all immunosuppressive drugs. An improved understanding of the biology of regulatory T cells will make it possible to replace current induction regimens with those favouring the selective vaccination of T cells that prevent graft rejection. Once regulation is established, the continued supply of graft antigens should empower T cell regulation to become the dominant natural mechanism to prevent graft rejection.     

Regulatory T cells in transplantation

There has recently been an explosion of renewed interest in regulatory T cells, particularly those within the CD4(+)CD25(+) population. It is becoming increasingly apparent that these cells exist not only as naturally occurring cells that may contribute to the maintenance of self-tolerance, but they also have the potential to prevent rejection of allografts in experimental models. Such cells have now been identified in humans as well as in rodents.     

Regulatory T cells and transplantation tolerance

In the past decade, several types of regulatory T cells (Tregs) have been identified to play a pivotal role in the control of autoimmunity and transplantation tolerance in rodents and in human beings, including innate regulatory NKT cells and gammadelta T cells, naturally occurring FoxP3 expressing CD4(+)CD25(+) T cells, and in-vitro induced Tregs including interleuking-10 (IL-10)-secreting Tr1 CD4(+) T cells, TGF-beta-producing Th3 CD4(+) T cells, anergic CD4(+) T cells, CD8(+)CD28(-) and CD3(+)CD4(-)CD8(-) T cells. Recent studies have shown that innate and adaptive Tregs may be linked and act in concert to mediate immunosuppression. As our understanding of regulatory T cell populations has substantially advanced, compelling evidence support the prospect that in-vitro expanded, patient-tailored Tregs with indirect anti-donor allospecificity could be potential reagents as adoptive cell therapy for individualized medicine to promote clinical transplantation tolerance.     

Regulatory T cell therapy for the induction of clinical organ transplantation tolerance

The pursuit of transplantation tolerance is the holygrail in clinical organ transplantation. It has been established that regulatory T cells (Tregs) can confer donor-specific tolerance in mouse models of transplantation. However, this is crucially dependent on the strain combination, the organ transplanted and most importantly, the ratio of Tregs to alloreactive effector T cells. The ex vivo expansion of Tregs is one solution to increase the number of alloantigen specific cells capable of suppressing the alloresponse. Indeed, ex vivo expanded, alloantigen specific murine Tregs are shown to preferentially migrate to, and proliferate in, the graft and draining lymph node. In human transplantation it has been proposed that depletion of the majority of direct pathway alloreactive T cells will be required to tip the balance in favour of regulation. Ex vivo expansion of alloantigen specific, indirect pathway human Tregs, which can cross regulate the residual direct pathway has been established. Rapid expansion of these cells is possible, whilst they retain antigen specificity, suppressive properties and favourable homing markers. Furthermore, considerable progress has been made to define which immunosuppressive drugs favour the expansion and function of Tregs. Currently a series of clinical trials of adoptive Treg therapy in combination with depletion of alloreactive T cells and short term immunosuppression are underway for human transplantation with the aim of minimizing immunosuppressive drugs and completely withdrawal.     

Regulatory T cell-mediated transplantation tolerance

The existence of naturally occurring regulatory T cells in normal hosts and their pivotal role in maintaining both auto- and allo-tolerance have direct implications on the therapy of autoimmune disorders and for achieving immunosuppression-free allotransplantation. Among the various forms of regulatory T cells described, CD4⁺CD25⁺ T cells have emerged as one of the most potent tolerogenic subsets. In this review, we discuss the molecular basis of development and function of these regulatory T cells and their potential role in the context of chronic lung allograft rejection. AB and RCF contributed equally to this work     

Regulatory T cells control autoimmunity following syngeneic bone marrow transplantation

Sublethally irradiated, immunodeficient, C57BL/6 RAG-2 gene-deleted recipient mice reconstituted with T cell-depleted bone marrow (BM) grafts frequently developed diarrhea, lost weight and showed signs of autoimmunity, dying between 4 and 7 weeks after reconstitution. Mice died despite evidence of efficient donor-derived hemato-lymphoid reconstitution, and disease was associated with the presence of IgG anti-nuclear antibodies. Autoimmunity was initiated by T cells, but could be prevented by transfer of naturally arising regulatory T cells. In contrast, lethally irradiated, BM-reconstituted immunocompetent, C57BL/6 mice survived without signs of autoimmunity. Survival of immunocompetent mice was shown to be due to the presence of residual, extra-thymically located, radio-resistant, functional regulatory T cells. The importance of regulatory T cells was further shown by the reduced survival of immunocompetent BM recipients whose CD25+ T cells had been depleted prior to bone marrow transplantation. The implications of these results in the context of syngeneic graft-versus-host disease following BM transplantation are discussed.     

Regulatory T cells

Regulatory T-cells are a subset of T cells that have beene extensively studied in modern immunology. They are important for the maintenance of peripheral tolerance, and have an important role in various clinical conditions such as allergy, autoimmune disorders, tumors, infections, and in transplant medicine. Basically, this population has a suppressive effect on the neighboring immune cells, thus contributing to the local modulation and control of immune response. There are two main populations of regulatory T cells - natural regulatory T cells, which form a distinct cellular lineage, develop in thymus and perform their modulatory action through direct intercellular contact, along with the secreted cytokines; and inducible regulatory T cells, which develop in the periphery after contact with the antigen that is presented on the antigen presenting cell, and their primary mode of action is through the interleukin 10 (IL-10) and transforming growth factor beta (TGF-alpha) cytokines. Natural regulatory T cells are activated through T cell receptor after contact with specific antigen and inhibit proliferation of other T cells in an antigen independent manner. One of the major difficulties in the research of regulatory T cells is the lack of specific molecular markers that would identify these cells. Natural regulatory T cells constitutively express surface molecule CD25, but many other surface and intracellular molecules (HLA-DR, CD122, CD45RO, CD62, CTLA-4, GITR, PD-1, Notch, FOXP3, etc.) are being investigated for further phenotypic characterization of these cells. Because regulatory T cells have an important role in establishing peripheral tolerance, their importance is manifested in a number of clinical conditions. In the IPEX syndrome (immunodysregulation, polyendocrinopathy and enteropathy, X-linked), which is caused by mutation in Foxp3 gene that influences the development and function of regulatory T cells, patients develop severe autoimmune reactions that involve autoimmune endocrine disorders (type 1 diabetes, thyroiditis), respiratory and nutritive allergy, eczema and severe infections. In different types of allergy (pollen allergy, dust mite, nutritive allergens, contact hypersensitivity, etc.) and autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis and type 1 diabetes) a lower number or decreased functional capability of regulatory T cells have been described. In inflammatory conditions and infections, this cell population has an important task in restricting immune response and protecting the host from excessive damage. This ability of regulatory T cells can be used by some pathogens (Epstein Barr virus, Mycobacterium tuberculosis, Leishmania major, etc.) and tumor cells to avoid host response and therefore contribute to the development of some pathological conditions. The knowledge gained on the phenotype and function of regulatory T cells could be useful in many medical conditions. In allergy, autoimmune diseases and in transplant procedures in medicine it would be desirable to increase their function, thus to partially suppress the immune system activity. On the other hand, in some infections and tumors, it would be preferable to decrease the activity of regulatory T cells and boost the function of effector T cells. Regulatory T cells comprise a very active field of immunology, therefore monitoring and modulating of their activity is of great potential significance in a broad spectrum of clinical conditions. By developing and standardizing methods for their monitoring, it would be possible to follow additional parameters of certain clinical conditions and possibly utilize them in therapy.     

Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms

Summary: Transplantation tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well‐characterized populations of T cells, demonstrating regulatory capacity: the ‘natural’ CD4⁺CD25⁺ T cells and the interleukin (IL)‐10‐producing Tr1 cells. Although both types of regulatory T cells can induce transplantation tolerance under appropriate conditions, it is not clear whether either one plays any role in drug‐induced dominant tolerance, primarily due to a lack of clear‐cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T‐cell and antigen‐presenting cell libraries to identify gene‐expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1‐like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4⁺CD25⁺ regulatory T cells from the spleen. DCs that were treated with the tolerance‐enhancing agents IL‐10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.     

调节性T细胞及相关细胞因子与同种小肠移植耐受

许多对于宿主免疫耐受中调节性T细胞作用的研究提供了大量有意义的结果。在小肠移植，抗CD4mAb和抗CD8mAbs均抑制排斥，但抗CD4mAb更有效；CD4^ CD25^T细胞的免疫抑制性表现在经TCR介导信号刺激活化以后能够抑制CD4^ 和CD8^ T细胞的活化和增殖，从而抑制排斥反应的发生实现耐受；调节性T细胞分泌的关键细胞因子与小肠移植排斥反应的发生、发展密切相关。通过少量关键的相关细胞因子改变免疫反应，成为实现同种小肠移植耐受的具有高度可行性的重要方法。     

Regulatory T cells in autologous stem cell transplantation for autoimmune disease

Since a decade autologous stem cell transplantation (ASCT) is successfully performed to treat patients with severe autoimmune disease. However, the mechanism of action of this intervention remains largely unknown. Scarce data from animal studies and human clinical trials indicate that, besides extensive immune ablation, restoration of regulatory immune networks is of critical importance. This review focuses on the role of naturally occurring and induced regulatory T cells in controlling immune reconstitution and restoration of immune tolerance and in preventing relapses of disease following ASCT.     

Regulatory T cells in autologous stem cell transplantation for autoimmune disease

Since a decade autologous stem cell transplantation (ASCT) is successfully performed to treat patients with severe autoimmune disease. However, the mechanism of action of this intervention remains largely unknown. Scarce data from animal studies and human clinical trials indicate that, besides extensive immune ablation, restoration of regulatory immune networks is of critical importance. This review focuses on the role of naturally occurring and induced regulatory T cells in controlling immune reconstitution and restoration of immune tolerance and in preventing relapses of disease following ASCT.     

Regulatory T cells and cancer

Increasing evidence indicates that T regulatory (Treg) cells have the potent ability to suppress host immune responses, thus preventing autoimmune diseases. However, recent studies demonstrate that tumor cells can recruit these Treg cells to inhibit antitumor immunity in the tumor microenvironment, thus limiting the efficiency of cancer immunotherapy. Tumor-specific Treg cells have recently been identified and characterized, providing compelling evidence that such antigen-specific Treg cells can induce tumor-specific local immune tolerance. Vaccine strategies designed to overcome tumor-associated immune suppression are crucial to successful immunotherapy. Recent findings indicate that Toll-like receptors directly regulate the suppressive activity of human Treg cells, which might offer new opportunities to improve the outcome of cancer immunotherapy by co-administration of certain Toll-like receptor ligands and antigenic peptides.     

Regulatory T cells and asthma

Airway inflammation in asthma is characterized by activation of T helper type-2 (Th2) T cells, IgE production and eosinophilia. In many cases, this process is related to an inappropriate T cell response to environmental allergens, and other T cell-dependent pathways may also be involved (such as Th17). Regulatory T cells (Tregs) are T cells that suppress potentially harmful immune responses. Two major subsets of Treg are CD25^hi, Foxp3⁺Tregs and IL-10-producing Tregs. There is evidence that the numbers or function of both subsets may be deficient in patients with atopic allergic disease. Recent work has extended these findings into the airway in asthma where Foxp3 expression was reduced and CD25^hi Treg-suppressive function was deficient. In animal models of allergic airways disease, Tregs can suppress established airway inflammation and airway hyperresponsiveness, and protocols to enhance the development, recruitment and function of Tregs have been described. Together with studies of patients and in vitro studies of human T cells, these investigations are defining potential interventions to enhance Treg function in the airway in asthma. Existing therapies including corticosteroids and allergen immunotherapy act on Tregs, in part to increase IL-10 production, while vitamin D3 and long-acting β-agonists enhance IL-10 Treg function. Other possibilities may be enhancement of Treg function via histamine or prostanoid receptors, or by blocking pro-inflammatory pathways that prevent suppression by Tregs (activation of Toll-like receptors, or production of cytokines such as IL-6 and TNF-α). As Tregs can also suppress the potentially beneficial immune response important for controlling infections and cancer, a therapeutic intervention should target allergen- or site-specific regulation.     

Regulatory T cells in stem cell transplantation: strategies and first clinical experiences

The adoptive transfer of donor-type CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) protects from graft-versus-host disease in murine bone marrow transplantation models. Results from first clinical trials exploring such strategies have recently been presented and seem to confirm the efficacy of Treg for the prevention of this severe complication after allogeneic stem cell transplantation. Further improvements in Treg isolation and in vitro expansion technologies will facilitate the broader exploration of Treg therapies, for example, for the treatment of ongoing graft-versus-host disease or the prevention of graft rejection after solid organ transplantation.     

Regulatory T cells and autoimmune disease

Summary: Although T‐cell clones bearing T‐cell receptors with high affinity for self‐peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T‐cell repertoire remains strongly biased toward self‐peptide MHC complexes and includes autoreactive T cells. A search for peripheral T cells that might exert dominant inhibitory effects on autoreactivity has implicated a subpopulation of CD4⁺CD25⁺ T cells called regulatory T cells (Tregs). Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease. Last, we discuss our recent definition of the potential role of B7 expressed on activated T‐effector cells as a target molecule for Treg‐dependent suppression. These observations suggest that the engagement of B7 on effector T cells transmits an inhibitory signal that blocks or attenuates effector T‐cell function. We restrict our comments to the suppression mediated by cells within the CD4 lineage; the impact of the cells within the CD8 lineage that may suppress via engagement of Qa‐1 on effector T cells is not addressed in this review.