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1.  Regulatory T cells vs Th17: differentiation of Th17 versus Treg, are the mutually exclusive? 
Naive CD4+ cells differentiate into T helper (Th1, Th2, Th9, Th17) and regulatory T (Treg) cells to execute their immunologic function. Whereas TGF-β suppresses Th1 and Th2 cell differentiation, this cytokine promotes Th9, Th17 and Foxp3+ regulatory T cells depending upon the presence of other cytokines. IL-6 promotes Th17, but suppresses regulatory T cell differentiation. Moreover, natural but not TGF-β-induced regulatory T cells convert into Th17 cells in the inflammatory milieu. Here an update of T cell differentiation and conversion, as well as underlying mechanisms are given.
PMCID: PMC3714204  PMID: 23885327
T helper cells; Th1; Th2; Th9; Th17; Tfh; Foxp3+ regulatory T cells; cytokine; differentiation; autoimmunity
3.  Cutting Edge: All-Trans Retinoic Acid Sustains the Stability and Function of Natural Regulatory T Cells in an Inflammatory Milieu 
Recent studies have demonstrated that plasticity of naturally occurring CD4+Foxp3+ regulatory T cells (nTregs) may account for their inability to control chronic inflammation in established autoimmune diseases. All-trans retinoic acid (atRA), the active derivative of vitamin A, has been demonstrated to promote Foxp3+ Treg differentiation and suppress Th17 development. In this study, we report a vital role of atRA in sustaining the stability and functionality of nTregs in the presence of IL-6. We found that nTregs treated with atRA were resistant to Th17 and other Th cell conversion and maintained Foxp3 expression and suppressive activity in the presence of IL-6 in vitro. atRA decreased IL-6R expression and signaling by nTregs. Of interest, adoptive transfer of nTregs even from arthritic mice treated with atRA suppressed progression of established collagen-induced arthritis. We suggest that nTregs treated with atRA may represent a novel treatment strategy to control established chronic immune-mediated inflammatory diseases.
doi:10.4049/jimmunol.1000598
PMCID: PMC3098624  PMID: 20679534
4.  Therapeutic potential of TGF-β-induced CD4+Foxp3+ regulatory T cells in autoimmune diseases 
Autoimmunity  2010;44(1):43-50.
Foxp3+ T regulatory cell (Treg) subsets play a crucial role in the maintenance of immune homeostasis against self-antigen. The lack or dysfunction of these cells is responsible for the pathogenesis and development of many autoimmune diseases. Therefore, manipulation of these cells may provide a novel therapeutic approach to treat autoimmune diseases. In this review, we provide current opinions concerning the classification, developmental and functional characterizations of Treg subsets. A particular emphasis will be focused on the therapeutic role of TGF-β-induced CD4+Foxp3+ cells (iTregs) in established autoimmune disease. Moreover, the similarity and disparity of iTregs and naturally occurring, thymus-derived CD4+CD25+Foxp3+ regulatory T cells (nTregs) have also be discussed. While the proinflammatory cytokine IL-6 can convert nTregs to IL-17-producing cells, iTregs induced by TGF-β are resistant to the effects of this cytokine. Understanding this difference may play a key role in determining how Tregs can be used in the treatment of established autoimmune diseases.
doi:10.3109/08916931003782163
PMCID: PMC4038306  PMID: 20670119
Autoimmune diseases; Immunoregulation; Regulatory T cells; TGF-β; Foxp3; Th17 cells
5.  Induced T Regulatory Cells Suppress Osteoclastogenesis and Bone Erosion in Collagen-induced Arthritis Better than Natural T Tegulatory Cells 
Annals of the rheumatic diseases  2012;71(9):1567-1572.
Objective
Osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA) and natural CD4+Foxp3+regulatory T cells (nTregs) can inhibit osteoclastogenesis. This study aims to determine whether TGF-β-induced CD4+Foxp3+regulatory T cells (iTregs) also suppress osteolastogenesis and bone erosion in collagen induced arthritis (CIA).
Methods
Osteoclasts were induced from bone-marrow CD11b+ cells with RANKL and macrophage colony-stimulating factor (M-CSF), and assessed with tartrate-resistant acid phosphatase (TRAP) staining. CD4+ iTregs were generated with TGF-β and added to cultures with different ratios with CD11b+ cells. Transwell and antibody blockade experiments were performed to define the mechanism of action. NF-kB activation was determined by western blot. 3×106 CD4+ iTregs, nTregs or control cells were adoptively transferred to DBA1/J mice on day 14 after immunization with CII/CFA. CIA onset and severity were monitored and bone erosion was examined by CT scan.
Results
Both CD4+ Tregs almost completely suppressed osteoclastogenesis but only iTregs sustained the effect in the presence of IL-6 in vitro. CD4+ iTregs but not nTregs and control cells injected after immunization and before of onset of CIA significantly suppressed disease development. Of note, CT scan showed that the joints in CD4+ iTregs but not nTregs or control cells infused CIA had less bone erosion. Treatment with CD4+ iTregs but not other cells dramatically decreased the levels of NF-kB p65/p50 in osteoclasts in vitro and P65/50 and RANKL expression by synovial tissues in vivo.
Conclusion
Manipulation of CD4+ iTregs may have therapeutic effects on rheumatoid arthritis and other bone erosion related diseases.
doi:10.1136/annrheumdis-2011-201052
PMCID: PMC4038329  PMID: 22764040
6.  Induction of antigen-specific immune tolerance by TGF-β-induced CD4+Foxp3+ regulatory T cells 
Like natural CD4+CD25+ Treg cells, TGF-β-induced Treg cells also prevent allograft rejection in MHC-mismatched organ transplantation models. In analyzing this effect with greater detail, we determined that injection of TGF-β-induced, alloactivated CD4+CD25+ cells induces antigen-specific immune tolerance in vivo. Increased CD4+CD25+ cells in recipients contribute to this immune tolerance. In addition, adoptive transfer of TGF-β-induced CD4+CD25+ cells did not result in significant toxic and side effects in recipients. These results indicate that TGF-β-induced, alloactivated CD4+CD25+ cells may provide a safe and effective approach to protect MHC-mismatched organ grafts from rejection in a clinical setting.
PMCID: PMC2770184  PMID: 19918314
TGF-β; Foxp3; regulatory T cells; Immunoregulation; transplant tolerance
7.  Emerging role of Interleukin-22 in autoimmune diseases 
Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren’s syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.
doi:10.1016/j.cytogfr.2012.07.002
PMCID: PMC4003867  PMID: 22906768
IL-22; Th17; Th22; autoimmune; therapeutic
8.  The development and function of Follicular helper T cells in immune responses 
Cellular & molecular immunology  2012;9(5):375-379.
Follicular helper T cells (Tfh) have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset development, like other lineages, is dependent on microenvironment where a particular transcriptional program is initiated. It has been shown that Bcl-6 and IL-21 act as master regulators for the development and function of Tfh cells. Tfh dysregulation is involved in the development of autoimmune pathologies, such as systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases. The present review highlights the recent advances in the field of Tfh cells and focus on their development and function.
doi:10.1038/cmi.2012.18
PMCID: PMC4000446  PMID: 22659733
autoimmune diseases; follicular helper T cells; systemic lupus erythematousus
9.  The Critical Role of TGF-β1 in the Development of Induced Foxp3+ Regulatory T Cells 
Foxp3+T regulatory cell (Treg) subsets play a crucial role in the maintenance of immune homeostasis against self-antigen. The lack or dysfunction of these cells is responsible for the pathogenesis and development of many autoimmune diseases. Therefore, manipulation of these cells may provide a novel therapeutic approach to treat autoimmune diseases and prevent allograft rejection during organ transplantation. In the article, we will provide current opinions concerning the classification, developmental and functional characterizations of Treg subsets. A particular emphasis will be focused on transforming cell growth factor beta (TGF-β) and its role in the differentiation and development of induced regulatory T cells (iTregs) in the periphery. Moreover, the similarity and disparity of iTregs and naturally occurring, thymus-derived CD4+CD25+Foxp3+ regulatory T cells (nTregs) will also be discussed. While proinflammatory cytokine IL-6 can convert nTregs to IL-17-producing cells, peripheral Tregs induced by TGF-β are resistant to this cytokine. This difference may affect the role of each in the adaptive immune response.
PMCID: PMC2592590  PMID: 19079658
Immunoregulation; regulatory T cells; TGF-β; Foxp3; Th17 cells
10.  Neutralization of IL-4 and IFN-γ Facilitates inducing TGF-β-induced CD4+Foxp3+ Regulatory Cells 
It has been well recognized that TGF-β is able to induce CD4+CD25+Foxp3+ suppressor/regulatory T (iTreg) cells and IL-2 facilitates iTreg induction and expansion, however, only half of TGF-β-induced CD4+CD25+ cells express Foxp3 and remaining CD4+CD25+Foxp3- cells may represent effector cells. Whether other factor(s) can increase Foxp3 expression by CD4+CD25+ cells induced with TGF-β is still unclear. Here we show that addition of exogenous IFN-γ or IL-4 diminished the ability of TGF-β to induce Foxp3 expression and IL-2 failed to rescue this decreased Foxp3 expression. Conversely, neutralization of IFN-γ and IL-4 significantly enhanced the ability of TGF-β to induce Foxp3 and develop the suppressive activity, indicating that different cytokine profiles affect the differentiation of CD4+CD25+Foxp3+ subset induced by TGF-β. These results show that combination of antibodies against IFN-γ and IL-4 and TGF-β enhances the efficacy of generation and function of iTreg cells and may therefore provide a novel therapeutic strategy for the treatment of autoimmune and other chronic inflammatory diseases.
PMCID: PMC3614670  PMID: 23675066
suppressor/regulatory T cells; cytokine; Foxp3; autoimmunity
11.  Treg cells: a potential regulator for IL-22 expression? 
Inteleurkin-22 (IL-22) is a IL-10 family cytokine member and is mainly produced by innate lymphoid cells (ILCs), Th17 cells, and Th22 cells. Previous studies have indicated that IL-23 and several transcription factors, including STAT3, RORγt, and the AhR are important stimulus. Recently, there is emerging evidence that Tregs can regulate IL-22 expression. In the review, we discuss the updated advancement on Tregs function and its regulatory role on IL-22 expression.
PMCID: PMC3925892  PMID: 24551268
Interleukin-22; regulatory (Treg) cells; T helper cells; innate immune cells
12.  Regulatory T cells and B cells: implication on autoimmune diseases 
The regulatory T (Treg) cells play an important role in the maintenance of homeostasis and the prevention of autoimmune diseases. Although most studies are focusing on the role of Treg cells in T cells and T cells-mediated diseases, these cells also directly affect B cells and other non-T cells. This manuscript updates the role of Treg cells on the B cells and B cell-mediated diseases. In addition, the mechanisms whereby Treg cells suppress B cell responses have been discussed.
PMCID: PMC3843247  PMID: 24294353
Treg; Foxp3; B cells; antibodies; autoimmune diseases
13.  A Mouse Model of Adoptive Immunotherapeutic Targeting of Autoimmune Arthritis Using Allo-Tolerogenic Dendritic Cells  
PLoS ONE  2013;8(10):e77729.
Objective
Tolerogenic dendritic cells (tDCs) are immunosuppressive cells with potent tolerogenic ability and are promising immunotherapeutic tools for treating rheumatoid arthritis (RA). However, it is currently unknown whether allogeneic tDCs (allo-tDCs) induce tolerance in RA, and whether the numbers of adoptively transferred allo-tDCs, or the requirement for pulsing with relevant auto-antigens are important.
Methods
tDCs were derived from bone marrow precursors of C57BL/B6 mice, which were induced in vitro by GM-CSF, IL-10 and TGF-β1. Collagen-induced arthritis (CIA) was modeled in D1 mice by immunization with type II collagen (CII) to test the therapeutic ability of allo-tDCs against CIA. Clinical and histopathologic scores, arthritic incidence, cytokine and anti-CII antibody secretion, and CD4+Th subsets were analyzed.
Results
tDCs were characterized in vitro by a stable immature phonotype and a potent immunosuppressive ability. Following adoptive transfer of low doses (5×105) of CII-loaded allo-tDCs, a remarkable anti-arthritic activity, improved clinical scores and histological end-points were found. Serological levels of inflammatory cytokines and anti-CII antibodies were also significantly lower in CIA mice treated with CII-pulsed allo-tDCs as compared with allo-tDCs. Moreover, treatment with allo-tDCs altered the proportion of Treg/Th17 cells.
Conclusion
These findings suggested that allo-tDCs, especially following antigen loading, reduced the severity of CIA in a dose-dependent manner. The dampening of CIA was associated with modulated cytokine secretion, Treg/Th17 polarization and inhibition of anti-CII secretion. This study highlights the potential therapeutic utility of allo-tDCs in autoimmune arthritis and should facilitate the future design of allo-tDC immunotherapeutic strategies against RA.
doi:10.1371/journal.pone.0077729
PMCID: PMC3812020  PMID: 24204938
14.  Dendritic cell-specific disruption of TGFβ receptor II leads to altered regulatory T-cell phenotype and spontaneous multi-organ autoimmunity 
In vitrodata and transgenic mouse models suggest a role for TGFβ signaling in dendritic cells (DC) to prevent autoimmunity primarily through maintenance of DCs in their immature and tolerogenic state characterized by low expression of MHCII and co-stimulatory molecules, and increased expression of indoleamine 2,3-dioxygenase (IDO), among others. To test whether a complete lack of TGFβ signaling in DCs predisposes mice to spontaneous autoimmunity, and to verify the mechanisms implicated previously in vitro, we generated conditional knock-out mice with Cre-mediated DC-specific deletion of Tgfbr2 (DC-Tgfbr2 KO). DC-Tgfbr2 KO mice die before 15 weeks of age with multi-organ autoimmune inflammation and spontaneous activation of T and B cells. Interestingly, there were no significant differences in the expression of MHCII, co-stimulatory molecules, or IDO in secondary lymphoid organ DCs, although Tgfbr2-deficient DCs were more pro-inflammatory in vitro and in vivo. DC-Tgfbr2 KO showed attenuated FoxP3 expression in regulatory T cells (Tregs) and abnormal expansion of CD25−FoxP3+ Tregs in vivo. Tgfbr2-deficient DCs secreted elevated levels of IFNγ and were not capable of directing antigen-specific Treg conversion unless in the presence of anti-IFNγ blocking antibody. Adoptive transfer of iTregs into DC-Tgfbr2 KO mice partially rescued the phenotype. Therefore, in vivo, TGFβ signaling in DCs is critical in the control of autoimmunity through both Treg dependent and independent mechanisms, but it does not affect MHCII and co-stimulatory molecule expression.
doi:10.4049/jimmunol.1201029
PMCID: PMC3466393  PMID: 22972928
16.  Blockade of IL-1R signaling diminishes Paneth cell depletion and Toxoplasma gondii induced ileitis in mice 
Interleukin 1 is a critical inflammatory mediator and involved in host defense to several pathogens. Oral T. gondii infection causes lethal ileitis in C57BL/6 (BL6) mice and serves to investigate the mechanisms of acute intestinal inflammation. Here we show that IL-1 is expressed upon oral T. gondii (76K strain) infection in the small intestine and mediates ileitis as IL-1R1 deficient mice have reduced neutrophil recruitment in the lamina propria, parasite invasion, inflammatory lesions and enhanced survival as compared to BL6 infected control mice. Protection in the absence of IL-1R1 signaling was associated with reduced IFN-γ expression and preserved Paneth cells, while these cells were eliminated in infected BL6 mice. Furthermore, blockade of IL-1 by IL-1β antibody attenuated inflammation in BL6 mice. In conclusion, IL-1 signaling contributes to the inflammatory response with increase IFN-γ expression and Paneth cell depletion upon oral T. gondii infection.
PMCID: PMC3714202  PMID: 23885328
Toxoplasma gondii; IL-1R1 receptor signaling; Paneth neutralizing antibody; inflammation; innate immunity
17.  Advances in distinguishing natural from induced Foxp3+ regulatory T cells 
For more than a decade now, the regulatory T (Treg) cell has widely been considered as a critical subpopulation of T cells which can suppress effector T cell responses as well as suppressing the activity of other immune cells, such as mast cell, dendritic cells, and B cells. Treg cells have been broadly characterized as comprising of two main populations: thymus-derived natural Treg (nTreg) cells, and peripherally generated induced Treg (iTreg) cells. Both subsets have similar phenotypic characteristics and comparable suppressive function against T cell-mediated immune response and diseases. However, both Foxp3 positive Treg subsets exhibit some specific differences such as different mRNA transcripts and protein expression, epigenetic modification, and stability. These subtle differences reinforce the notion that they represent unique and distinct subsets. Accurately distinguishing iTregs from nTregs will help to clarify the biological features and contributions of each Treg subsets in peripheral tolerance, autoimmunity and tumor immunity. One difficult problem is that it has not been possible to distinguish iTregs from nTregs using surface markers until two recent articles were published to address this possibility. This review will focus on very recent advances in using molecular markers to differentiate these Treg subsets.
PMCID: PMC3544233  PMID: 23329997
Treg; Foxp3; Helios; neuropilin 1
18.  Polyclonal CD4+Foxp3+ Treg cells induce TGFβ-dependent tolerogenic dendritic cells that suppress the murine lupus-like syndrome 
Interplay between Foxp3+ regulatory T cells (Treg) and dendritic cells (DCs) maintains immunologic tolerance, but the effects of each cell on the other are not well understood. We report that polyclonal CD4+Foxp3+ Treg cells induced ex vivo with transforming growth factor beta (TGFβ) (iTreg) suppress a lupus-like chronic graft-versus-host disease by preventing the expansion of immunogenic DCs and inducing protective DCs that generate additional recipient CD4+Foxp3+ cells. The protective effects of the transferred iTreg cells required both interleukin (IL)-10 and TGFβ, but the tolerogenic effects of the iTreg on DCs, and the immunosuppressive effects of these DCs were exclusively TGFβ-dependent. The iTreg were unable to tolerize Tgfbr2-deficient DCs. These results support the essential role of DCs in ‘infectious tolerance’ and emphasize the central role of TGFβ in protective iTreg/DC interactions in vivo.
doi:10.1093/jmcb/mjs040
PMCID: PMC3523557  PMID: 22773728
regulatory T cells; dendritic cells; TGFβ; graft-versus-host disease
19.  Plasmacytoid Dendritic Cells Are Inefficient in Activation of Human Regulatory T Cells 
PLoS ONE  2012;7(8):e44056.
Background
Dendritic cells (DC) play a key role in initiation and regulation of immune responses. Plasmacytoid DC (pDC), a small subset of DC, characterized as type-I interferon producing cells, are critically involved in anti-viral immune responses, but also mediate tolerance by induction of regulatory T cells (Treg). In this study, we compared the capacity of human pDC and conventional DC (cDC) to modulate T cell activity in presence of Foxp3+ Treg.
Principal Findings
In coculture of T effector cells (Teff) and Treg, activated cDC overcome Treg anergy, abrogate their suppressive function and induce Teff proliferation. In contrast, pDC do not break Treg anergy but induce Teff proliferation even in coculture with Treg. Lack of Treg-mediated suppression is independent of proinflammatory cytokines like IFN-α, IL-1, IL-6 and TNF-α. Phenotyping of pDC-stimulated Treg reveals a reduced expression of Treg activation markers GARP and CTLA-4. Additional stimulation by anti-CD3 antibodies enhances surface expression of GARP and CTLA-4 on Treg and consequently reconstitutes their suppressive function, while increased costimulation with anti-CD28 antibodies is ineffective.
Conclusions/Significance
Our data show that activated pDC induce Teff proliferation, but are insufficient for functional Treg activation and, therefore, allow expansion of Teff also in presence of Treg.
doi:10.1371/journal.pone.0044056
PMCID: PMC3430613  PMID: 22952871
20.  Interleukin-1 as an Injury Signal Mobilizes Retinyl Esters in Hepatic Stellate Cells through Down Regulation of Lecithin Retinol Acyltransferase 
PLoS ONE  2011;6(11):e26644.
Retinoids are mostly stored as retinyl esters in hepatic stellate cells (HSCs) through esterification of retinol and fatty acid, catalyzed by lecithin-retinol acyltransferase (LRAT). This study is designated to address how retinyl esters are mobilized in liver injury for tissue repair and wound healing. Initially, we speculated that acute inflammatory cytokines may act as injury signal to mobilize retinyl esters by down-regulation of LRAT in HSCs. By examining a panel of cytokines we found interleukin-1 (IL-1) can potently down-regulate mRNA and protein levels of LRAT, resulting in mobilization of retinyl esters in primary rat HSCs. To simulate the microenvironment in the space of Disse, HSCs were embedded in three-dimensional extracellular matrix, by which HSCs retaine quiescent phenotypes, indicated by up-regulation of LRAT and accumulation of lipid droplets. Upon IL-1 stimulation, LRAT expression went down together with mobilization of lipid droplets. Secreted factors from Kupffer cells were able to suppress LRAT expression in HSCs, which was neutralized by IL-1 receptor antagonist. To explore the underlying mechanism we noted that the stability of LRAT protein is not significantly regulated by IL-1, indicating the regulation is likely at transcriptional level. Indeed, we found that IL-1 failed to down-regulate recombinant LRAT protein expressed in HSCs by adenovirus, while transcription of endogenous LRAT was promptly decreased. Following liver damage, IL-1 was promptly elevated in a close pace with down-regulation of LRAT transcription, implying their causative relationship. After administration of IL-1, retinyl ester levels in the liver, as measured by LC/MS/MS, decreased in association with down-regulation of LRAT. Likewise, IL-1 receptor knockout mice were protected from injury-induced down-regulation of LRAT. In summary, we identified IL-1 as an injury signal to mobilize retinyl ester in HSCs through down-regulation of LRAT, implying a mechanism governing transition from hepatic injury to wound healing.
doi:10.1371/journal.pone.0026644
PMCID: PMC3208544  PMID: 22073179
21.  BAFF Promotes Th17 Cells and Aggravates Experimental Autoimmune Encephalomyelitis 
PLoS ONE  2011;6(8):e23629.
Background
BAFF, in addition to promoting B cell survival and differentiation, may affect T cells. The objective of this study was to determine the effect of BAFF on Th17 cell generation and its ramifications for the Th17 cell-driven disease, EAE.
Methodology/Principal Findings
Th17 cells were increased in BAFF-Tg B6 (B6.BTg) mice and decreased in B6.Baff−/− mice. Th17 cells in B6.Baff−/− mice bearing a BAFF Tg (B6.Baff−/−.BTg mice) were identical to those in B6.BTg mice, indicating that membrane BAFF is dispensable for Th17 cell generation as long as soluble BAFF is plentiful. In T + non-T cell criss-cross co-cultures, Th17 cell generation was greatest in cultures containing B6.BTg T cells and lowest in cultures containing B6.Baff−/− T cells, regardless of the source of non-T cells. In cultures containing only T cells, Th17 cell generation followed an identical pattern. CD4+ cell expression of CD126 (IL-6R α chain) was increased in B6.BTg mice and decreased in B6.Baff−/− mice, and activation of STAT3 following stimulation with IL-6 + TGF-β was also greatest in B6.BTg cells and lowest in B6.Baff−/− cells. EAE was clinically and pathologically most severe in B6.BTg mice and least severe in B6.Baff−/− mice and correlated with MOG35–55 peptide-induced Th17 cell responses.
Conclusions/Significance
Collectively, these findings document a contribution of BAFF to pathogenic Th17 cell responses and suggest that BAFF antagonism may be efficacious in Th17 cell-driven diseases.
doi:10.1371/journal.pone.0023629
PMCID: PMC3163640  PMID: 21897850
22.  Generation of human regulatory T cells de novo with suppressive function prevent xenogeneic graft versus host disease 
International immunopharmacology  2010;11(5):630-637.
Treatment with rapamycin (RAPA) favorably affects regulatory T cells (Treg) in vivo, and RAPA induces the de novo expression of FOXP3 in murine alloantigen-specific T cells. Whether RAPA acts independently or with transforming growth factor beta (TGF-β) to produce ex vivo-induced Treg generation is unknown. Naïve CD4+ T cells isolated from peripheral blood mononuclear cells were stimulated with anti-CD3/CD28 coated beads in the presence of IL-2 for 5 to 7 days. Ten ng/ml of TGF-β (1 to 100 ng/mL RAPA) was added to some of the cultures. The phenotypes were analyzed with flow cytometry. The conditioned cells were cocultured with CFSE-labeled T cells in different ratios for 5 days. CFSE dilution indicating T response cell proliferation was analyzed by flow cytometry. Xenogeneic graft-versus-host disease (x-GVHD) was induced by transplanting human peripheral blood mononuclear cells into RAG2−/− γc−/− mice exposed to total body irradiation, and various factors in the subjects were subsequently compared. CD4 cells induced by rapamycin and TGF-β (CD4RAPA/TGF-β) expressed the natural Treg phenotypes and trafficking receptors, and no significant cytotoxicity was observed. CD4RAPA/TGF-β was anergic and demonstrated potent suppressive activity in vitro. Although the transfer of human peripheral blood mononuclear cells into RAG2−/− γc−/− mice caused x-GVHD, the cotransfer of CD4RAPA/TGF-β decreased human cell engraftment and extended survival in mice. RAPA plus TGF-β induces human naïve T cells to become suppressor cells, a novel strategy for treating human autoimmune diseases and preventing allograft rejection.
doi:10.1016/j.intimp.2010.11.036
PMCID: PMC3099130  PMID: 21147213
Regulatory T cells; TGF-β; Rapamycin; Graft-versus host disease; Human
23.  Involvement of CD226+ NK Cells in Immunopathogenesis of Systemic Lupus Erythematosus 
Dysfunction of immune systems, including innate and adaptive immunity, is responsible for the immunopathogenesis of systemic lupus erythematosus (SLE). NK cells are a major part of the innate immune system, and diminished populations of NK cells have been reported in SLE patients. However, the mechanisms behind this decrease and the role of NK cells in SLE pathogenesis remain poorly understood. In this study, we found that a deficiency of NK cells, especially CD226+ NK cells, is prominent in patients with active SLE. Meanwhile, expression of the CD226 ligands CD112 and CD155 on plasmacytoid dendritic cells is observed in SLE patients; thus, activation of CD226+ NK cells may be induced by CD226–ligand interactions. Furthermore, IFN-α, which is mainly produced by plasmacytoid dendritic cells, can mediate the activation-induced cell death of NK cells. Therefore, these processes likely contribute to the loss of NK cells in patients with active SLE. Despite the impaired cytotoxicity of peripheral NK cells in human SLE patients and mouse SLE models, we provide evidence that CD226+ NK cells infiltrate the kidneys of predisease MRL-lpr/lpr mice. Kidney-infiltrating NK cells displayed an activated phenotype and a marked ability to produce cytotoxic granules. These results suggest that, before apoptosis, activated NK cells can infiltrate tissues and, to some extent, mediate tissue injury by producing cytotoxic granules and immunoregulatory cytokines.
doi:10.4049/jimmunol.1000569
PMCID: PMC3097030  PMID: 21296979
24.  Antigen-non-specific regulation centered on CD25+Foxp3+ Treg cells 
Cellular & molecular immunology  2010;7(6):414-418.
CD4+CD25+Foxp3+ regulatory T cells (Tregs) are of special interest in immunology because of their potent inhibitory function. Many fundamental aspects of Tregs, including their antigenic profile, development and peripheral homeostasis, remain highly controversial. Here, we propose a Treg-centered antigen-non-specific immunoregulation model focused on the T-cell system, particularly on CD4+ T cells. The T-cell pool consists of naive T cells (Tnais), Tregs and effector T cells (Teffs). Regardless of antigen specificity, the ratio of the activated T-cell subsets (Treg/Teff/Tnai) and their temporal and spatial uniformity dictate the differentiation of Tnais. Activated Tregs inhibit the activation, proliferation, induction and activity of Teffs; in contrast, activated Teffs inhibit the induction of Tregs from Tnais but cooperate with Treg-specific antigens to promote the proliferation and activity of Tregs. In many cases, these interactions are antigen-non-specific, whereas the activation of both Tregs and Teffs is antigen-specific. Memory T-cell subsets are essential for the maintenance of adaptive immune responses, but the antigen-non-specific interactions among T-cell subsets may be more important during the establishment of the adaptive immune system to a newly encountered antigen. This is especially important when new and memory antigens are presented closely—both temporally and spatially—to T cells, because there are always baseline levels of activated Tregs, which are usually higher than levels of memory T cells for new antigens. Based on this hypothesis, we further infer that, under physiological conditions, Tregs in lymph nodes mainly recognize antigens frequently released from draining tissues, and that these self-reactive Tregs are commonly involved in the establishment of adaptive immunity to new antigens and in the feedback control of excessive responses to pathogens.
doi:10.1038/cmi.2010.39
PMCID: PMC3094156  PMID: 20729905
antigen; immune regulation; tolerance; Treg
25.  Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells 
Whereas TGF-β is essential for the development of peripherally induced Foxp3+ regulatory T cells (iTreg cells) and Th17 cells, the intracellular signaling mechanism by which TGF-β regulates development of both cell subsets is less understood. In this study, we report that neither Smad2 nor Smad3 gene deficiency abrogates TGF-β–dependent iTreg induction by a deacetylase inhibitor trichostatin A in vivo, although the loss of the Smad2 or Smad3 gene partially reduces iTreg induction in vitro. Similarly, SMAD2 and SMAD3 have a redundant role in development of Th17 in vitro and in experimental autoimmune encephalomyelitis. In addition, ERK and/or JNK pathways were shown to be involved in regulating iTreg cells, whereas the p38 pathway predominately modulated Th17 and experimental autoimmune encephalomyelitis induction. Therefore, selective targeting of these intracellular TGF-β signaling pathways during iTreg and Th17 cell development might lead to the development of therapies in treating autoimmune and other chronic inflammatory diseases.
doi:10.4049/jimmunol.0903418
PMCID: PMC3087811  PMID: 20304828

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