Treg Plasticity Research Articles

Atherosclerosis-Driven Treg Plasticity Results in Formation of a Dysfunctional Subset of Plastic IFNγ+ Th1/Tregs.

Forkhead box P3+ T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Evidence suggests that Tregs respond to environmental cues to permit or suppress inflammation. In atherosclerosis, Th1-driven inflammation affects Treg homeostasis, but the mechanisms governing this phenomenon are unclear. Here, we address whether atherosclerosis impacts Treg plasticity and functionality in Apoe-/- mice, and what effect Treg plasticity might have on the pathology of atherosclerosis. We demonstrate that atherosclerosis promotes Treg plasticity, resulting in the reduction of CXCR3+ Tregs and the accumulation of an intermediate Th1-like interferon (IFN)-γ+CCR5+ Treg subset (Th1/Tregs) within the aorta. Importantly, Th1/Tregs arise in atherosclerosis from bona fide Tregs, rather than from T-effector cells. We show that Th1/Tregs recovered from atherosclerotic mice are dysfunctional in suppression assays. Using an adoptive transfer system and plasticity-prone Mir146a-/- Tregs, we demonstrate that elevated IFNγ+ Mir146a-/- Th1/Tregs are unable to adequately reduce atherosclerosis, arterial Th1, or macrophage content within Apoe-/- mice, in comparison to Mir146a+/+ Tregs. Finally, via single-cell RNA-sequencing and real-time -polymerase chain reaction, we show that Th1/Tregs possess a unique transcriptional phenotype characterized by coexpression of Treg and Th1 lineage genes and a downregulation of Treg-related genes, including Ikzf2, Ikzf4, Tigit, Lilrb4, and Il10. In addition, an ingenuity pathway analysis further implicates IFNγ, IFNα, interleukin-2, interleukin-7, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), T-cell receptor, and Csnk2b-related pathways in regulating Treg plasticity. Atherosclerosis drives Treg plasticity, resulting in the accumulation of dysfunctional IFNγ+ Th1/Tregs that may permit further arterial inflammation and atherogenesis.

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs.

Although major advancements have made in investigating the aetiology of SLE (systemic lupus erythaematosus), the role of MDSCs (myeloid-derived suppressor cells) in SLE progression remains confused. Recently, some studies have revealed that MDSCs play an important role in lupus mice. However, the proportion and function of MDSCs in lupus mice and SLE patients are still poorly understood. In the present study, we investigated the proportion and function of MDSCs using different stages of MRL/lpr lupus mice and specimens from SLE patients with different activity. Results showed that splenic granulocytic (G-)MDSCs were significantly expanded by increasing the expression of CCR1 (CC chemokine receptor 1) in diseased MRL/lpr lupus mice and in high-disease-activity SLE patients. However, the proportion of monocytic (M-)MDSCs remains similar in MRL/lpr lupus mice and SLE patients. G-MDSCs produce high levels of ROS (reactive oxygen species) through increasing gp91(phox) expression, and activated TLR2 (Toll-like receptor 2) and AIM2 (absent in melanoma 2) inflammasome in M-MDSCs lead to IL-1β (interleukin 1β) expression in diseased MRL/lpr mice and high-disease-activity SLE patients. Previous study has revealed that MDSCs could alter the plasticity of Th17 (T helper 17) cells and Tregs (regulatory T-cells) via ROS and IL-1β. Co-culture experiments showed that G-MDSCs impaired Treg differentiation via ROS and M-MDSCs promoted Th17 cell polarization by IL-1β invitro Furthermore, adoptive transfer or antibody depletion of MDSCs in MRL/lpr mice confirmed that MDSCs influenced the imbalance of Tregs and Th17 cells invivo Our results indicate that MDSCs with the capacity to regulate Th17 cell/Treg balance may be a critical pathogenic factor in SLE.

Abstract 447: Atherosclerosis-driven Treg Plasticity Results in the Formation of a Dysfunctional Subset of Plastic IFNg + Th1/Tregs

Foxp3 + T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Emerging evidence suggests that Tregs respond to environmental cues to permit or suppress inflammation. In atherosclerosis, Th1-driven inflammation affects Treg homeostasis, but the mechanisms governing this phenomenon are unclear. Here, we addressed whether atherosclerosis impacts Treg plasticity or functionality in Apoe -/- mice and what effect Treg plasticity might have on the pathology of atherosclerosis. We demonstrate that atherosclerosis promotes Treg plasticity, resulting in the reduction of CXCR3 + Tregs, and the accumulation of an intermediate Th1-like IFNγ + CCR5 + Treg subset (Th1/Tregs) within the arterial wall. Using Foxp3 Gfp/Gfp and Foxp3 Yfp-cre/Yfp-cre Rosa tdTomato/tdTomato lineage tracing mice, we demonstrate that Th1/Tregs arise in atherosclerosis from bona fide Tregs, rather than T effector cells. Th1/Tregs recovered from atherosclerotic mice are dysfunctional in suppression assays. Importantly, using Mir146a -/- mice, we demonstrate that plasticity-prone Mir146 -/- Tregs fail to reduce atherosclerosis, arterial Th1, or macrophage content in Apoe -/- recipients. Lastly, we utilized single cell RNA-sequencing to gain whole transcriptome information on Th1/Tregs, Treg, and Th1 cells. Th1/Tregs yielded a unique transcriptional phenotype characterized by co-expression of Treg and Th1 lineage genes, and down-regulation of Treg-related genes, including Ikzf2 , Ikzf4, Tigit, and Lilrb4 . Additionally, an ingenuity pathway analysis further implicates IFNγ, IFNα, IL-2, IL-7, CTLA4, T cell receptor, and Csnk2b-related pathways in regulating Treg plasticity. In conclusion, atherosclerosis drives Treg plasticity, resulting in the accumulation of dysfunctional IFNγ + Th1/Tregs that permit further arterial inflammation and atherogenesis.

Pathogenic conversion of Foxp3+ T cells into Th1 and Th17 cells in Stromal Keratitis

Abstract Ocular infection with herpes simplex virus 1 (HSV-1) can result in a chronic immuno-inflammatory lesion that is a significant cause of human blindness. IFN-γ producing CD4 + T cells are generally considered the main orchestrators, and lesions are more severe if the regulatory T cell (Treg) response is compromised. Tregs have been shown to lose FoxP3 (Treg lineage factor) and adopt alternate lineage fates in a changing cytokine environment. Moreover, little is known about the stability of Treg cells in an ongoing inflammatory reaction such as is the case of SK. In this study-using fate mapping mice, we were able to demonstrate that the population of ex-Tregs increased at the site of infection that is the cornea and also at the secondary lymphoid organs after HSV-1 infection. In vivo studies showed that these ex-Tregs acquired the Th1 and Th17 phenotype, which may play a destructive role in stromal keratitis. We also demonstrate in vivo that CD25lo subset of Tregs is less suppressive and more prone to conversion than CD25hi Tregs. Additionally, in-vitro studies suggested that Tregs in the presence of IL-12 converted into ex-Tregs, however this plasticity was prevented when Tregs were generated in the presence of DNMT inhibitor (Azacytidine). Thus, plasticity of Tregs might represent a problem during SK, which needs to be controlled with appropriate therapeutic procedures. Overall, our results indicate that Tregs lose FoxP3 expression in ocular inflammatory setting and drugs that reverse Treg plasticity could be useful to restore Treg function and to inhibit ocular immunopathology.

Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin

AbstractSelf-tolerance and immune homeostasis are orchestrated by FOXP3+ regulatory T cells (Tregs). Recent data have revealed that upon stimulation, Tregs may exhibit plasticity toward a proinflammatory phenotype, producing interleukin 17 (IL-17) and/or interferon γ (IFN-γ). Such deregulation of Tregs may contribute to the perpetuation of inflammatory processes, including graft-versus-host disease. Thus, it is important to identify immunomodulatory factors influencing Treg stability. Platelet-derived microparticles (PMPs) are involved in hemostasis and vascular health and have recently been shown to be intimately involved in (pathogenic) immune responses. Therefore, we investigated whether PMPs have the ability to affect Treg plasticity. PMPs were cocultured with healthy donor peripheral blood–derived Tregs that were stimulated with anti-CD3/CD28 monoclonal antibodies in the presence of IL-2, IL-15, and IL-1β. PMPs prevented the differentiation of peripheral blood–derived Tregs into IL-17– and IFN-γ–producing cells, even in the presence of the IL-17–driving proinflammatory cytokine IL-1β. The mechanism of action by which PMPs prevent Treg plasticity consisted of rapid and selective P-selectin–dependent binding of PMPs to a CCR6+HLA-DR+ memory-like Treg subset and their ability to inhibit Treg proliferation, in part through CXCR3 engagement. The findings that ∼8% of Tregs in the circulation of healthy individuals are CD41+P-selectin+ and that distinct binding of patient plasma PMPs to Tregs was observed support in vivo relevance. These findings open the exciting possibility that PMPs actively regulate the immune response at sites of (vascular) inflammation, where they are known to accumulate and interact with leukocytes, consolidating the (vascular) healing process.

Interleukin-10 deficiency impairs regulatory T cell-derived neuropilin-1 functions and promotes Th1 and Th17 immunity.

Regulatory T cells (Tregs) expand in peripheral lymphoid organs and can produce immunosuppressive cytokines to support tumor growth. IL-10 abrogation efficiently induces Treg formation but dampens tumoral neuropilin-1 (Nrp-1) Treg signaling, which simultaneously augments Th1 and Th17 immunity. These effects are associated with the plasticity and stability of Tregs and effector T cell functions that can limit tumorigenesis. Within the tumor microenvironment, there appears to be a “mutual antagonism” between immunoenhancement and immunosuppression mechanisms, eventually leading to decreased metastasis. In contrast, tumor progression is paralleled by a reduction in Nrp-1-producing Tregs controlled by the IL-10 and TGF-β1 levels. However, Th1, Th17 and Treg immunity is primarily regulated by IL-10 or Nrp-1 and not TGF-β1 except when combined with IL-10. These results emphasize the important implications for the therapeutic use of Tregs. The number of Treg cells must be maintained in a healthy and dynamic homeostatic range to prevent malignant diseases. Moreover, Treg-mediated immunosuppression can be limited by reducing tumor-derived Treg Nrp-1 levels.

T regulatory cell mediated immunotherapy for solid organ transplantation: A clinical perspective.

T regulatory cells (Tregs) play a vital role in suppressing heightened immune responses, and thereby promote a state of immunological tolerance. Tregs modulate both innate and adaptive immunity, which make them a potential candidate for cell-based immunotherapy to suppress uncontrolled activation of graft specific inflammatory cells and their toxic mediators. These grafts specific inflammatory cells (T effector cells) and other inflammatory mediators (Immunoglobulins, active complement mediators) are mainly responsible for graft vascular deterioration followed by acute/chronic rejection. Treg mediated immunotherapy is under investigation to induce allospecific tolerance in various ongoing clinical trials in organ transplant recipients. Treg immunotherapy is showing promising results but the key issues regarding Treg immunotherapy are not yet fully resolved including their mechanism of action, and specific Treg cell phenotype responsible for a state of tolerance. This review highlights the involvement of various subsets of Tregs during immune suppression, novelty of Tregs functions, effects on angiogenesis, emerging technologies for effective Treg expansion, plasticity and safety associated with clinical applications. Altogether this information will assist in designing single/combined Treg mediated therapies for successful clinical trials in solid organ transplantations.

The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome

T-helper 17 (Th17) and T-regulatory (Treg) cells are frequently found at barrier surfaces, particularly within the intestinal mucosa, where they function to protect the host from pathogenic microorganisms and to restrain excessive effector T-cell responses, respectively. Despite their differing functional properties, Th17 cells and Tregs share similar developmental requirements. In fact, the fate of antigen-naïve T-cells to either Th17 or Treg lineages is finely regulated by key mediators, including TGFβ, IL-6, and all-trans retinoic acid. Importantly, the intestinal microbiome also provides immunostimulatory signals, which can activate innate and downstream adaptive immune responses. Specific components of the gut microbiome have been implicated in the production of proinflammatory cytokines by innate immune cells, such as IL-6, IL-23, IL-1β, and the subsequent generation and expansion of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of intestinal Tregs that can actively induce mucosal tolerance. As such, dysbiosis of the gut microbiome may not solely represent a consequence of gut inflammation, but rather shape the Treg/Th17 commitment and influence susceptibility to inflammatory bowel disease. In this review, we discuss Treg and Th17 cell plasticity, its dynamic regulation by the microbiome, and highlight its impact on intestinal homeostasis and disease.

Pathological conditions re-shape physiological Tregs into pathological Tregs

CD4+FOXP3+ regulatory T cells (Tregs) are a subset of CD4 T cells that play an essential role in maintaining peripheral immune tolerance, controlling acute and chronic inflammation, allergy, autoimmune diseases, and anti-cancer immune responses. Over the past 20 years, a significant progress has been made since Tregs were first characterized in 1995. Many concepts and principles regarding Tregs generation, phenotypic features, subsets (tTregs, pTregs, iTregs, and iTreg35), tissue specificity (central Tregs, effector Tregs, and tissue resident Tregs), homeostasis (highly dynamic and apoptotic), regulation of Tregs by receptors for PAMPs and DAMPs, Treg plasticity (re-differentiation to other CD4 T helper cell subsets, Th1, Th2, Tfh, and Th17), and epigenetic regulation of Tregs phenotypes and functions have been innovated. In this concise review, we want to briefly analyze these eight new progresses in the study of Tregs. We have also proposed for the first time a novel concept that “physiological Tregs” have been re-shaped into “pathological Tregs” in various pathological environments. Continuing of the improvement in our understanding on this important cellular component about the immune tolerance and immune suppression would lead to the future development of novel therapeutics approaches for acute and chronic inflammatory diseases, allergy, allogeneic transplantation-related immunity, sepsis, autoimmune diseases, and cancers.

Control of IFN-γ production and regulatory function by the inducible nuclear protein IκB-ζ in T cells

The transcriptional regulator IκB-ζ is important for the control of apoptosis in keratinocytes. Thus, IκB-ζ-deficient mice develop autoimmune diseases, such as Sjögren's syndrome. However, T cells also play a pivotal role in Sjögren's syndrome. To study the role of IκB-ζ in T cells, we generated T cell-specific, IκB-ζ-deficient mice. We observed increased numbers of peripheral effector/memory CD4(+) cells and IFN-γ-producing CD4(+) cells in 3-week-old mice. We found that IκB-ζ can be up-regulated by TGF-β1 in naïve CD4(+) T cells and that it negatively regulates IFN-γ expression. In addition, we generated Treg-specific, IκB-ζ deficient mice and found that IκB-ζ is dispensable for the plasticity and stability of Tregs. However, Tregs from T cell-specific, IκB-ζ-deficient mice have reduced immunoregulatory function. Thus, our data reveal a previously unappreciated role for IκB-ζ in IFN-γ production in T cells and the immunoregulatory function of Tregs.

Once a Treg, always a Treg?

Regulatory T cells (Tregs) prevail as a specialized cell lineage that has a central role in the dominant control of immunological tolerance and maintenance of immune homeostasis. Thymus-derived Tregs (tTregs) and their peripherally induced counterparts (pTregs) are imprinted with unique Forkhead box protein 3 (Foxp3)-dependent and independent transcriptional and epigenetic characteristics that bestows on them the ability to suppress disparate immunological and non-immunological challenges. Thus, unidirectional commitment and the predominant stability of this regulatory lineage is essential for their unwavering and robust suppressor function and has clinical implications for the use of Tregs as cellular therapy for various immune pathologies. However, recent studies have revealed considerable heterogeneity or plasticity in the Treg lineage, acquisition of alternative effector or hybrid fates, and promotion rather than suppression of inflammation in extreme contexts. In addition, the absolute stability of Tregs under all circumstances has been questioned. Since these observations challenge the safety and efficacy of human Treg therapy, the issue of Treg stability versus plasticity continues to be enthusiastically debated. In this review, we assess our current understanding of the defining features of Foxp3(+) Tregs, the intrinsic and extrinsic cues that guide development and commitment to the Treg lineage, and the phenotypic and functional heterogeneity that shapes the plasticity and stability of this critical regulatory population in inflammatory contexts.

Regulatory T cells in rheumatoid arthritis showed increased plasticity toward Th17 but retained suppressive function in peripheral blood

ObjectiveRegulatory T cells (Tregs) with the plasticity of producing proinflammatory cytokine IL-17 have been demonstrated under normal and pathogenic conditions. However, it remains unclear whether IL-17-producing Tregs lose their suppressive...

SOCS1 and regulation of regulatory T cells plasticity.

Several reports have suggested that natural regulatory T cells (Tregs) lose Forkhead box P3 (Foxp3) expression and suppression activity under certain inflammatory conditions. Treg plasticity has been studied because it may be associated with the pathogenesis of autoimmunity. Some studies showed that a minor uncommitted Foxp3+ T cell population, which lacks hypomethylation at Treg-specific demethylation regions (TSDRs), may convert to effector/helper T cells. Suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling, has been reported to play an important role in Treg cell integrity and function by protecting the cells from excessive inflammatory cytokines. In this review, we discuss Treg plasticity and maintenance of suppression functions in both physiological and pathological settings. In addition, we discuss molecular mechanisms of maintaining Treg plasticity by SOCS1 and other molecules. Such information will be useful for therapy of autoimmune diseases and reinforcement of antitumor immunity.

CD39/CD73 and the imbalance of Th17 cells and regulatory T cells in allergic asthma

In the immune system, CD4+CD25+Foxp3+ regulatory T cells (Tregs) maintain self‑tolerance and Th17 cells mediate inflammatory responses. CD39 is expressed on the surface of a subset of naturally occurring human Tregs that are important in constraining pathogenic Th17 cells. Additional studies have shown that Tregs differentiate into interleukin‑17 (IL‑17)+Foxp3+ T cells. Our previous study indicated an imbalance of Th17 and Tregs in allergic asthma; however, the underlying mechanisms remain poorly understood. Using quantitative PCR (qPCR), CD39 and CD73 mRNA levels in CD4+ T cells were investigated. Flow cytometry was used to analyze the proportion of IL‑17+Foxp3+ T cells, and CD39 and CD73 expressed by CD4+ T cells and Tregs in the peripheral blood of the subjects. The results of the present study demonstrated an increased frequency of CD4+Foxp3+IL‑17+ T cells in moderate to severe asthma. A deficiency in CD39 expressed on the surface of CD4+ T cells and Tregs was observed in asthma patients. The expression of CD39 and CD73 on the surface of CD4+ T cells and Tregs was negatively correlated with the number of Th17 cells. These results indicated that the plasticity of Tregs transforming to IL‑17+Foxp3+CD4+ T cells, the reduced frequency of CD39+ Tregs and less effective suppression of IL‑17 production by residual CD39+ Tregs leads to an imbalance of Th17 and Tregs in asthma. Therefore, enhanced CD39 activity is hypothesized to prevent the progression of asthma.

The Role of FOXP3 in Regulating Immune Responses

Regulatory T cells (Tregs) act in trans to control immune responses. The suppressive function of Tregs relies heavily on high and stable expression of the transcription factor FOXP3, which, together with other transcription factors, activates anti-inflammatory genes and represses proinflammatory genes. FOXP3 is required to shape the unique signaling mechanisms in Tregs, creating a positive-feedback pathway to further enhance its own expression. In addition, FOXP3 is thought to switch on a complex transcriptional network that leads to the stabilization of the Treg phenotype. Emerging data reveal that FOXP3 achieves this function in concert with several other transcription factors, many of which are associated with lineages of conventional T cells. In this review, we will discuss the structural features of FOXP3 and how it functions by interacting with other transcription factors. We will also summarize the role of FOXP3 in establishing the unique signaling cascades in Tregs. Finally, we will dissect the cooperative roles of FOXP3 and other T-cell lineage-defining transcription factors and discuss how these networks not only control the ability to Tregs to suppress different types of immune responses, but also enable Treg plasticity.

Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis

Defective development and function of CD4(+)CD25(high+)Foxp3(+) regulatory T cells (Tregs) contribute to the pathogenesis of psoriasis and other autoimmune diseases. Little is known about the influence of adhesions molecules on the differentiation of Foxp3(+) Tregs into proinflammatory Th17 cells occurring in lesional skin and blood of psoriasis patients. In the CD18(hypo) PL/J mouse model of psoriasis, reduced expression of CD18/β2 integrin to 2-16% of wild-type levels is associated with progressive loss of Tregs, impaired cell-cell contact between Tregs and dendritic cells (DCs), as well as Treg dysfunction as reported earlier. In the present investigation, Tregs derived from CD18(hypo) PL/J mice were analyzed for their propensity to differentiate into IL-17-producing Th17 cells in vivo and in in vitro Treg-DC cocultures. Adoptively transferred CD18(hypo) PL/J Tregs were more inclined toward conversion into IL-17-producing Th17 cells in vivo in an inflammatory as well as noninflammatory environment compared with CD18(wt) PL/J Tregs. Addition of neutralizing Ab against CD18 to Treg-DC cocultures in vitro promoted conversion of CD18(wt) PL/J Tregs to Th17 cells in a dose-dependent manner similar to conversion rates of CD18(hypo) PL/J Tregs. Reduced thymic output of naturally occurring Tregs and peripheral conversion of Tregs into Th17 cells therefore both contribute to the loss of Tregs and the psoriasiform dermatitis observed in CD18(hypo) PL/J mice. Our data overall indicate that CD18 expression levels impact Treg development as well as Treg plasticity and that differentiation of Tregs into IL-17-producing Th17 cells is distinctly facilitated by a subtotal deficiency of CD18.

T Cell Receptor Stimulation-Induced Epigenetic Changes and Foxp3 Expression Are Independent and Complementary Events Required for Treg Cell Development

The transcription factor Foxp3 is essential for the development of regulatory T (Treg) cells, yet its expression is insufficient for establishing the Treg cell lineage. Here we showed that Treg cell development was achieved by the combination of two independent processes, i.e., the expression of Foxp3 and the establishment of Treg cell-specific CpG hypomethylation pattern. Both events were induced by T cell receptor stimulation. The Treg cell-type CpG hypomethylation began in the thymus and continued to proceed in the periphery and could be fully established without Foxp3. The hypomethylation was required for Foxp3(+) T cells to acquire Treg cell-type gene expression, lineage stability, and full suppressive activity. Thus, those T cells in which the two events have concurrently occurred are developmentally set into the Treg cell lineage. This model explains how Treg cell fate and plasticity is controlled and can be exploited to generate functionally stable Treg cells.

Altered generation of induced regulatory T cells in the FVB.mdr1a-/- mouse model of colitis.

The FVB.mdr1a(-/-) mouse, lacking the small molecule pump P-glycoprotein (P-gp), is a commonly used model for the study of spontaneous T cell-mediated colitis. In addition, MDR1 polymorphisms and P-gp deficiency in humans have been linked to the development of ulcerative colitis. We now demonstrate that mice with P-gp deficiency have decreased levels of Foxp3(+) regulatory T cells (Tregs) in the intestinal lamina propria. This decrease is not due to either increased Treg apoptosis, altered Treg trafficking, or enhanced Treg plasticity to become Foxp3(+)IL-17(+) cells. Instead, P-gp deficiency appears to restrict the development of induced Treg cells (iTregs), as fewer Foxp3(+) iTregs developed from naive FVB.mdr1a(-/-) T cells both upon transforming growth factor-β (TGF-β) treatment in vitro and after adoptive transfer into FVB.rag2(-/-) recipients. Rather, in vitro TGF-β treatment results in a IL-17(+)CD4(+) T cell. This failure of iTregs to develop explains the decrease in Foxp3(+) Tregs in the FVB.mdr1a(-/-) intestine, representing a need to investigate this novel disease mechanism in human inflammatory bowel disease patients with MDR1 polymorphisms.

Tregs

Transfer of human regulatory T cells (Tregs) has become an attractive therapeutic alternative to improve the long-term outcome in transplantation and thus reduce the side-effects of conventional immunosuppressive drugs. Here, we summarize the recent findings on human Treg subsets, their phenotype and in-vivo function. In the last 2 years, it has become apparent that several Treg subsets exist that specifically regulate Th1-driven, Th2-driven, or Th17-driven immune responses; these subsets are very unstable and rapidly change their phenotype, for example, there is loss of Foxp3 expression upon extensive ex-vivo expansion and only the administration of rapamycin has been shown to be able to interfere reproducibly. New humanized mouse models incorporating human solid-organ grafts have been developed, which have been used to test the human Treg in-vivo function, and the first human Treg-cell products have been tested for safety and efficacy in stem cell transplantation. With the recent findings, we have gained a better understanding of Treg heterogeneity, plasticity and function. Using the outcomes of clinical trials in stem cell transplantation, we have learned that adoptive therapy of Tregs is well tolerated and we are now awaiting the first result in solid-organ transplantation from the 'ONE Study'.

Significance of T helper 17 immunity in transplantation

The aim of this review is to provide an overview of significance of T helper 17 (Th17) immunity in acute, chronic and antibody-mediated allograft rejection. The role of Th17 immunity in development of de-novo autoimmunity following transplantation is outlined. It will also consider the impact of Th17 immunity on transplantation tolerance. Potential therapies to target Th17 immunity are discussed. Interleukin17 (IL-17) is produced by a wide variety of immune and non-immune cells in response to injury. IL-17 production by tubular epithelial cells in response to complement activation in acute antibody-mediated rejection may perpetuate immune injury. Th17-dependent de-novo autoimmunity contributes to chronic allograft rejection. Targeting IL-17 not only inhibits Th17 immunity but also attenuates Th1 immunity by affecting the initial recruitment of immune cells to sites of inflammation and modulates innate and adaptive immune responses that ultimately lead to tissue destruction. Th17 immunity is now beginning to be appreciated as a set of responses mediated not only by CD4 Th17 cells but a variety of immune cells and a plethora of cytokines that collaborate to mediate immune disorders, including transplant rejection. Development and contribution of de-novo autoimmunity to chronic rejection is increasingly appreciated. The developmental plasticity of Tregs and Th17 cells is a major hurdle to Treg-based cellular therapies for transplantation. Several biologics targeting Th17 immunity are under evaluation for autoimmune disease. It remains to be determined whether these can be used in transplantation to improve outcomes.