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Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system with demyelination, axon damage, and paralysis. Induction of mixed chimerism with allogeneic donors has been shown to not cause graft-versus-host disease (GVHD) in animal models and humans. We have reported that induction of MHC-mismatched mixed chimerism can cure autoimmunity in autoimmune NOD mice, but this approach has not yet been tested in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). Here, we report that MHC-mismatched mixed chimerism with C57BL/6 (H-2b) donor in SJL/J (H-2s) EAE recipients eliminates clinical symptoms and prevents relapse. This cure is demonstrated by not only disappearance of clinical signs but also reversal of autoimmunity; elimination of infiltrating T, B, and macrophage cells in the spinal cord; and regeneration of myelin sheath. The reversal of autoimmunity is associated with a marked reduction of autoreactivity of CD4+ T cells and significant increase in the percentage of Foxp3+ Treg among host-type CD4+ T cells in the spleen and lymph nodes. The latter is associated with a marked reduction of the percentage of host-type CD4+CD8+ thymocytes and an increase of Treg percentage among the CD4+CD8+ and CD4+CD8- thymocytes. Thymectomy leads to loss of prevention of EAE relapse by induction of mixed chimerism, although there is a dramatic expansion of host-type Treg cells in the lymph nodes. These results indicate that induction of MHC-mismatched mixed chimerism can restore thymic negative selection of autoreactive CD4+ T cells, augment production of Foxp3+ Treg, and cure EAE. [ABSTRACT FROM AUTHOR]

The ligand activated transcription factor aryl hydrocarbon receptor (AhR) has been studied for many decades in toxicology as the ligand for the environmental contaminant dioxin. However, AhR has recently emerged as a critical physiological regulator of immune responses affecting both innate and adaptive systems, and several AhR ligands with different pharmacological profiles have recently been studied. The current review discusses new insights into the role of AhR signalling and AhR ligands on the regulation of the immune system, with a focus on regulatory T cells which maintain immune tolerance. Notably, AhR is expressed and modulates the development of two induced regulatory CD4+ T cell subsets, the forkhead box P3-positive (Foxp3+) regulatory T cells (iTreg) and the IL-10-secreting type 1 regulatory T (TR1) cells, through different signalling pathways. We will finally discuss how AhR ligands could be exploited to alleviate human autoimmune diseases. Clearly, drugs targeted against AhR should promote the development of new strategies to fight against autoimmune diseases.

Several studies have documented that dietary modifications influence the development of type 1 diabetes. However, little is known about the interplay of dietary components and the penetration of diabetes incidence. In this study we tested if wheat gluten is able to induce differences in the cytokine pattern of Foxp3+ regulatory T cells, as well as Foxp3− T cells, isolated from intestinal mucosal lymphoid tissue and non-mucosal lymphoid compartments in BALB/c mice. The gluten-containing standard diet markedly changed the cytokine expression within Foxp3− T cells, in all lymphoid organs tested, towards a higher expression of pro-inflammatory interferon-γ ( IFN-γ), interleukin-17 ( IL-17) and IL-2. In Foxp3+ regulatory T cells, gluten ingestion resulted in a mucosal increase in IL-17 and IL-2 and an overall increase in IFN-γ and IL-4. The gluten-free diet induced an anti-inflammatory cytokine profile with higher proportion of transforming growth factor-β ( TGF-β)+ Foxp3− T cells in all tested lymphoid tissues and higher IL-10 expression within non-T cells in spleen, and a tendency towards a mucosal increase in TGF-β+ Foxp3+ regulatory T cells. Our data shows that the gluten-containing standard diet modifies the cytokine pattern of both Foxp3− T cells and Foxp3+ regulatory T cells towards a more inflammatory cytokine profile. This immune profile may contribute to the higher type 1 diabetes incidence associated with gluten intake. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GvHD) remains a major complication after allogeneic hematopoietic stem-cell-transplantation. Present GvHD prophylaxis and treatment is still based on unspecific immunosuppressive drug therapy. Over the last decade, the potential of cell-based therapies involving the infusion of regulatory T cells has emerged as a feasible alternative approach for the treatment and prevention of GvHD. Here we review current efforts to translate data obtained in rodent models into clinical trials. Special emphasis is placed on the variety of strategies to generate sufficient numbers of alloantigen-specific regulatory T cells for adoptive cell therapy. This can be achieved either by expansion or by induction of a regulatory phenotype in naive T cells. Stability of the immunosuppressive phenotype of transferred regulatory T cells even in the highly inflammatory environment of acute GvHD will be thereby a critical parameter for actual therapeutic application. [ABSTRACT FROM AUTHOR]

Despite the improvements in transplant immunology and clinical and supportive care, graft-versus-host disease (GVHD) is still among the most common causes of overall mortality and morbidity after allogeneic hematopoietic cell transplantation. The development and severity of GVHD are strongly related with post-transplant outcomes. New strategies should be explored to overcome GVHD. Regulatory T cells (Treg cells), as dedicated suppressors of diverse immune responses and inflammation and important gatekeepers of immune homeostasis, contribute to the prevention of graft rejection and induce transplantation tolerance. Foxp3, a transcription factor, is predominantly expressed in Treg cells and is a master regulator of the development and function of Treg cells. Foxp3 mutations and Foxp3 deficiency lead to lethal autoimmune lymphoproliferative disease, which results from a defect in Treg cells. TGF-β1 is required to maintain Foxp3 expression in Treg cells. We isolated a novel population from among CD34 cells in our laboratory, referred to as human umbilical cord blood-derived stromal cells (hUCBDSCs), which exert an immunosuppressive effect and can notably increase Foxp3 expression in Treg cells. Our previous study also revealed that hUCBDSCs constantly secrete TGF-β1. Based on the literature searchings and our experimental findings, we hypothesize that hUCBDSCs, which secrete a high level of TGF-β1, modulate the Foxp3 expression of Treg cells through the TGF-β1/Smad3 pathway to regulate GVHD. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are a subpopulation of T cells that are specialized in suppressing immune responses. Here we show that the arginine methyl transferase protein PRMT5 can complex with FOXP3 transcription factors in Tregs. Mice with conditional knock out (cKO) of PRMT5 expression in Tregs develop severe scurfy-like autoimmunity. In these PRMT5 cKO mice, the spleen has reduced numbers of Tregs, but normal numbers of Tregs are found in the peripheral lymph nodes. These peripheral Tregs that lack PRMT5, however, display a limited suppressive function. Mass spectrometric analysis showed that FOXP3 can be di-methylated at positions R27, R51, and R146. A point mutation of Arginine (R) 51 to Lysine (K) led to defective suppressive functions in human CD4 T cells. Pharmacological inhibition of PRMT5 by DS-437 also reduced human Treg functions and inhibited the methylation of FOXP3. In addition, DS-437 significantly enhanced the anti-tumor effects of anti-erbB2/neu monoclonal antibody targeted therapy in Balb/c mice bearing CT26Her2 tumors by inhibiting Treg function and induction of tumor immunity. Controlling PRMT5 activity is a promising strategy for cancer therapy in situations where host immunity against tumors is attenuated in a FOXP3 dependent manner.

Background/aim: Recently CD4 + CD49b + LAG3 + regulatory T (Tr1) cells are reported to be IL-10 driven, have strong regulatory activities. Thus, this study aimed to investigate whether Treg and Tr1 cells participate in immunological status against cancer., Patients and Methods: Peripheral blood was withdrawn from patients (n=78), and healthy volunteers as controls (n=23). The peripheral blood mononuclear cells were subjected to FACScan analysis after labeling with anti-CD4, -CD25, - Foxp3, -CD49b and -LAG3 antibodies. Resected specimens were stained for IL-10. Patients' clinical course and clinicopathological factors were compared., Results: Tr1 was significantly higher in patients with cancer (p=0.02). Among patients who underwent R0 resection, those with early recurrence had a significantly higher pre-/post-operative Tr1 ratio (p<0.05). Median pre-/post-operative ratios of Foxp3Tregs and Tr1s predicted early recurrence with 85.6% sensitivity and 93.3% specificity. Disease-free survival was significantly lower in patients with high IL-10 expression in resected specimens., Conclusion: Peripheral Tregs and Tr1 indicate immunological state against cancer., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Prophylactic and/or therapeutic vaccines have an important potential to control Trypanosoma cruzi ( T. cruzi )infection. The involvement of regulatory/suppressor immune cells after an immunization treatment and T. cruzi infection has never been addressed. Here we show that a new trans-sialidase-based immunogen (TSf) was able to confer protection, correlating not only with beneficial changes in effector immune parameters, but also influencing populations of cells related to immune control. Regarding the effector response, mice immunized with TSf showed a TS-specific antibody response, significant delayed-type hypersensitivity (DTH) reactivity and increased production of IFN-γ by CD8+ splenocytes. After a challenge with T. cruzi , TSf-immunized mice showed 90% survival and low parasitemia as compared with 40% survival and high parasitemia in PBS-immunized mice. In relation to the regulatory/suppressor arm of the immune system, after T. cruzi infection TSf-immunized mice showed an increase in spleen CD4+ Foxp3+ regulatory T cells (Treg) as compared to PBS-inoculated and infected mice. Moreover, although T. cruzi infection elicited a notable increase in myeloid derived suppressor cells (MDSC) in the spleen of PBS-inoculated mice, TSf-immunized mice showed a significantly lower increase of MDSC. Results presented herein highlight the need of studying the immune response as a whole when a vaccine candidate is rationally tested., Competing Interests: CONFLICTS OF INTEREST None of the authors have a conflict of interest in relation to the content of the present work.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system with demyelination, axon damage, and paralysis. Induction of mixed chimerism with allogeneic donors has been shown to not cause graft-versus-host disease (GVHD) in animal models and humans. We have reported that induction of MHC-mismatched mixed chimerism can cure autoimmunity in autoimmune NOD mice, but this approach has not yet been tested in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE). Here, we report that MHC-mismatched mixed chimerism with C57BL/6 (H-2(b)) donor in SJL/J (H-2(s)) EAE recipients eliminates clinical symptoms and prevents relapse. This cure is demonstrated by not only disappearance of clinical signs but also reversal of autoimmunity; elimination of infiltrating T, B, and macrophage cells in the spinal cord; and regeneration of myelin sheath. The reversal of autoimmunity is associated with a marked reduction of autoreactivity of CD4(+) T cells and significant increase in the percentage of Foxp3(+) Treg among host-type CD4(+) T cells in the spleen and lymph nodes. The latter is associated with a marked reduction of the percentage of host-type CD4(+)CD8(+) thymocytes and an increase of Treg percentage among the CD4(+)CD8(+) and CD4(+)CD8(-) thymocytes. Thymectomy leads to loss of prevention of EAE relapse by induction of mixed chimerism, although there is a dramatic expansion of host-type Treg cells in the lymph nodes. These results indicate that induction of MHC-mismatched mixed chimerism can restore thymic negative selection of autoreactive CD4(+) T cells, augment production of Foxp3(+) Treg, and cure EAE.