Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1

The differentiation of naive CD4⁺ T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (T_H1) cells and antiinflammatory Foxp3⁺ regulatory T cells (T_reg cells). Genetic deletion of SIRT1 in DCs restrained the generation of T_reg cells while driving T_H1 development, resulting in an enhanced T-cell–mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal T_H1 and T_reg lineage commitment through DC-derived IL-12 and TGF-β1. Our studies implicates a DC-based SIRT1–HIF1α metabolic checkpoint in controlling T-cell lineage specification.CD4⁺ T cells are essential components of the adaptive immune system that regulate immune responses against foreign antigen. Upon antigen recognition, naive CD4⁺ T cells undergo activation and expansion, and, depending on inflammatory contexts and cytokine milieus, differentiate into functional and phenotypic T helper (T_H) subsets characterized by distinct cytokine production profile and function (1–3). T_H1 cells produce IFN-γ and elicit cellular immunity in responding to intracellular pathogens; T_H2 cells produce IL-4 and IL-5 and promote humoral immunity in responding to extracellular bacteria and helminthes; and T_H17 cells produce IL-17 and mediate antifungal defense and inflammation (4, 5). Additionally, regulatory T cells, often known as “induced regulatory T cells” (iT_reg cells), which act in synergy with naturally occurring T_reg cells (nT_reg cells), produce IL-10 and TGF-β1 and dampen immune responses elicited from T_H1, T_H2, and T_H17 (6–9).Dendritic cells (DCs), an essential component in the innate immune system, play a critical role in initiating front-line primary immune responses and directing subsequent pathogen-specific adaptive immune responses (2). In addition to presenting antigens and modulating cell surface costimulatory molecules, DC-derived cytokines and chemokines can result in either a proinflammatory or antiinflammatory environment, engaging distinct T-cell differentiation programs on naive CD4⁺ T cells (1, 10–16). For example, DC-producing IL-12 can support T_H1 development, whereas DC-producing IL-10 or TGF-β1 can support T_reg development. Recent studies from us and others have shown that innate signaling in DCs mediated by G protein-coupled receptor S1P1, the mitogen-activated kinases (MAPKs), and Wnt–β-catenin plays important roles in stimulating adaptive immune responses through directing native CD4⁺ T-cell differentiation (17–20). However, other critical signaling components in DCs that may play a role in shaping T-cell lineage engagement remain to be identified.SIRT1 is a mammalian homolog of the yeast NAD⁺-dependent protein deacetylase Sirt2, and plays a role in a variety of essential biological processes, including cell cycle progression, apoptosis, cell survival, gene silencing, heterochromatin formation, tumorigenesis, metabolism, and development (21, 22). SIRT1 has also been implicated in regulating immune responses. In T cells, SIRT1 is required to maintain T-cell tolerance (23, 24) and also play a role in inhibiting the function of T_reg cells in allograft survival (25). In myeloid cells, SIRT1 limits the inflammatory process by inhibiting the expression of proinflammatory cytokines (26, 27), while promoting DC maturation and T_H2 response in airway allergy (28). However, whether SIRT1 is involved in bridging the innate immune signal to adaptive immune response remains unexplored.Here, we found that SIRT1 plays a critical role in determining the T-cell lineage fate by directing DC-derived cytokine production, which links innate and adaptive immune modulation. Largely through a HIF1α–dependent signaling pathway, SIRT1 is required for the reciprocal production of IL-12 and TGF-β1 production in DCs as well as the expression of IL-12Rβ2 and TGF-βR2 in responding T cells, resulting in a differential lineage engagement of T_H1 and iT_reg in the microbial-induced inflammation.     

Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype

Osteopontin (OPN) has been shown to have T helper 1 (Th1) cytokine functions in cell-mediated immunity. Deficiency of OPN is linked to a reduced Th1 immune response in autoimmunity, infectious disease, and delayed-type allergy. Dendritic cells (DCs) are central for the induction of T-cell-mediated immunity, when initially flexible DCs are instructed by priming signals and tissue-derived factors to adopt Th1, Th2, or regulatory T-cell-inducing phenotypes. Although OPN influences the cytokine secretion of T cells and macrophages, its effects on DC polarization remain an important missing link in the understanding of OPN functions in Th1 immunity. Here we demonstrate that OPN promotes the emigration of human DCs from the epidermis and functionally activates myeloid-type DCs, augmenting their expression of HLA-DR, costimulatory, and adhesion molecules. OPN induces their Th1-promoting tumor necrosis factor alpha (TNF-alpha) and interleukin-12 (IL-12) secretion, and enhances their allostimulatory capacity. In mixed lymphocyte reactions (MLRs), OPN stimulates IL-12 secretion by DCs, inducing elevated interferon-gamma (IFN-gamma) production by T cells. Naive Th cells stimulated by OPN-activated DCs show a Th1-polarized cytokine production. Our findings identify OPN as an important tissue-derived factor that DCs encounter when traveling from peripheral sites of activation to secondary lymphatic organs, which induces DC maturation toward a Th1-promoting phenotype.     

Idiopathic inflammatory myopathies: from immunopathogenesis to new therapeutic targets

Pathogenesis of idiopathic inflammatory myositis (IIM) involves strong interactions between dendritic cells (DCs), activated Th1 and Th17 cells, B cells, muscle cells, genes and environment. Local maturation of DCs permit the activation and polarization of CD4+ T cells into T_H1 and T_H17 that play a key role in maintaining chronic muscle inflammation. T‐cell mediated myocytotoxicity promotes the liberation of specific muscle autoantigens from regenerating muscle cells with production of myositis‐specific autoantibodies. Type I interferon signature is a key characteristic of IIM. Type I IFN that can be induced by immune complexes containing myositis‐specific autoantibodies is produced by scattered plasmacytoid DCs but also by muscle cells particularly regenerating muscle cells. These immature muscle precursors appear to be critical in the pathogenesis of IIM as they up‐regulate muscle autoantigens, type I IFN, HLA class I antigens and TLR3‐7, all together involved in maintaining chronic muscle inflammation. In addition to the role of immune and muscle cells, genome‐wide association studies have confirmed the importance of several MHC and non‐MHC genes in IIM. Environmental factors can contribute to the pathogenesis of IIM. In sIBM, distinct features suggest both degenerative and inflammatory processes. In addition to our better understanding of the pathogenesis, identify molecular pathway leads to consider new targeted therapies including cytokine inhibition, B‐cell and T‐cell costimulation blockade, type I IFN neutralization or inhibition of the ubiquitin proteasome pathway.     

Les lymphocytes TH17 : différenciation, phénotype, fonctions, et implications en pathologie et thérapeutique humaine

Differentiation of naive CD4⁺ T helper (T_H) cells is a major step of the adaptative immune response. When activated by pathogens in a specific cytokine environment, CD4⁺ T cells differentiate into different subsets of T_H cells with specific effector functions. T_H1 lymphocytes orchestrate cellular immune response by producing interferon-γ and stimulating cytotoxic cells whereas T_H2 cells orchestrate humoral immune response by producing interleukin-4 (IL-4), IL-5 and IL-10, leading to immunoglobulin production. Conversely, regulatory T cells (Treg) are capable of inhibiting immune response. Recently discovered, T_H17 cells are characterized by their ability to produce IL-17 and play an important role in anti-infectious and inflammatory immune responses. This review focuses on present knowledge about T_H17 cells: their induction, phenotype, functions, implications in host defense and human disease, and their potential to represent possible therapeutic targets.     

Memory T cells: A helpful guard for allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHSCT) and the major cause of nonrelapse morbidity and mortality of AHSCT. In AHSCT, donor T cells facilitate hematopoietic stem cell (HSC) engraftment, contribute to anti-infection immunity, and mediate graft-versus-leukemia (GVL) responses. However, activated alloreactive T cells also attack recipient cells in vital organs, leading to GVHD. Different T-cell subsets, including naïve T (T_N) cells, memory T (T_M) cells, and regulatory T (T_reg) cells mediate different forms of GVHD and GVL; T_N cells mediate severe GVHD, whereas T_M cells do not cause GVHD, but preserve T-cell function including GVL. In addition, metabolic reprogramming controls T-cell differentiation and activation in these disease states. This minireview focuses on the role and the related mechanisms of T_M cells in AHSCT, and the potential manipulation of T cells in AHSCT.     

Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells

To exploit a novel strategy to regulate T cell-mediated immunity, we established human and murine modified dendritic cells (DCs) with potent immunoregulatory properties (designed as regulatory DCs), which displayed moderately high expression levels of major histocompatibility complex (MHC) molecules and extremely low levels of costimulatory molecules compared with their normal counterparts. Unlike human normal DCs, which caused the activation of allogeneic CD4(+) and CD8(+) T cells, human regulatory DCs not only induced their anergic state but also generated CD4(+) or CD8(+) regulatory T (Tr) cells from their respective naive subsets in vitro. Although murine normal DCs activated human xenoreactive T cells in vitro, murine regulatory DCs induced their hyporesponsiveness. Furthermore, transplantation of the primed human T cells with murine normal DCs into severe combined immunodeficient (SCID) mice enhanced the lethality caused by xenogeneic graft-versus-host disease (XGVHD), whereas transplantation of the primed human T cells with murine regulatory DCs impaired their ability to cause XGVHD. In addition, a single injection of murine regulatory DCs following xenogeneic or allogeneic transplantation protected the recipients from the lethality caused by XGVHD as well as allogeneic acute GVHD. Thus, the modulation of T cell-mediated immunity by regulatory DCs provides a novel therapeutic approach for immunopathogenic diseases.     

Prospects for dendritic cell vaccination against fungal infections in hematopoietic transplantation

Dendritic cells (DCs) are uniquely able to initiate and control the immune response to fungi. DCs function at three levels in the manipulation of the immune response to these pathogens. First, they mount an immediate or innate response to them, for example, by producing inflammatory mediators upon capture and phagocytosis; second, through these preceding innate functions, they decode the fungus-associated information and translate it in qualitatively different Th responses, and third, they are key in containing and dampening inflammatory responses by tolerization through the induction of regulatory T cells (Treg). DCs sense fungi in a morphotype-specific manner, through the engagement of distinct recognition receptors ultimately affecting cytokine production and costimulation. Both myeloid and plasmacytoid murine and human DCs phagocytose fungi and undergo functional maturation in response to them. However, their activation program for cytokine production was different, being IL-12 mainly produced by myeloid DCs and IL-12, IL-10 and IFN-alpha mainly produced by plasmacytoid DCs. This resulted in a distinct ability for T cell priming, being Th1, Th2, and Treg differently activated by the different DC subsets. The ability of fungus-pulsed DCs to prime for Th1 and Th2 cell activation upon adoptive transfer in vivo correlated with the occurrence of resistance and susceptibility to the infections, respectively. Antifungal protective immunity was also induced upon adoptive transfer of DCs transfected with fungal RNA. The efficacy was restricted to DCs transfected with RNA from yeasts or conidia but not with RNA from fungal hyphae. The effect was fungus-specific, as no cross-protection was observed upon adoptive transfer of DCs pulsed with either fungal species. The infusion of fungus-pulsed or RNA-transfected DCs accelerated the recovery of functional antifungal Th1 responses in mice with allogeneic hematopoietic stem cell transplantation (HSCT) and affected the outcome of the infections. As the ability of phagocytose fungi was defective in peripheral DCs from patients with HSCT, soon after the transplant, our findings suggest that the adoptive transfer of DCs may restore immunocompetence in HSCT by contributing to the educational program of T cells. Thus, the remarkable functional plasticity of DCs in response to fungi can be exploited for the deliberate targeting of cells and pathways of cell-mediated immunity in response to fungal vaccines.     

CpG DNA: a potent signal for growth, activation, and maturation of human dendritic cells.

DNA molecules containing unmethylated CpG-dinucleotides in particular base contexts ("CpG motifs") are excellent adjuvants in rodents, but their effects on human cells have been less clear. Dendritic cells (DCs) form the link between the innate and the acquired immune system and may influence the balance between T helper 1 (Th1) and Th2 immune responses. We evaluated the effects of CpG oligodeoxynucleotides alone or in combination with granulocyte-macrophage colony-stimulating factor (GMCSF) on different classes of purified human DCs. For primary dendritic precursor cells isolated from human blood, CpG oligonucleotides alone were superior to GMCSF in promoting survival and maturation (CD83 expression) as well as expression of class II MHC and the costimulatory molecules CD40, CD54, and CD86 of DCs. Both CD4-positive and CD4-negative peripheral blood dendritic precursor cells responded to CpG DNA which synergized with GMCSF but these DCs showed little response to lipopolysaccharide (LPS). In contrast, monocyte-derived DCs did not respond to CpG, but they were highly sensitive to LPS, suggesting an inverse correlation between CpG and LPS sensitivity in different subsets of DCs. Compared with GMCSF, CpG-treated peripheral blood DCs showed enhanced functional activity in the mixed lymphocyte reaction and induced T cells to secrete increased levels of Th1 cytokines. These findings demonstrate the ability of specific CpG motifs to strongly activate certain subsets of human DCs to promote Th1-like immune responses, and support the use of CpG DNA-based trials for immunotherapy against cancer, allergy, and infectious diseases.     

Dendritic cells in chronic obstructive pulmonary disease: new players in an old game

Dendritic cells (DCs) are professional antigen-presenting cells responsible for immune homeostasis. In the lung's responses to tissue damage or infection, they initiate and orchestrate innate and adaptive immunity. There are immature and mature states and at least three phenotypic and functional subsets. DCs circulate in the blood and localize to mucosal surfaces in immature form where they act as sentinels, sampling constituents of the external environment that breach the epithelium. With internalization of antigen, they are activated, mature, and migrate to draining lymph nodes to induce the proliferation and regulate the balance of Th1/Th2 T cells or to induce a state of tolerance, the last dependent on maturation status, extent of cell surface costimulatory molecule expression, and cytokine release. Cigarette smoke has modulatory effects varying with species, dose, the location examined within the lung, and the marker or technique used to identify DCs. Healthy smokers (and smokers with asthma) have reduced numbers of large airway mature DCs. In chronic obstructive pulmonary disease, the number of immature DCs is increased in small airways, whereas in smokers with chronic obstructive pulmonary disease, the total number of DCs appears to be reduced in large airways. We hypothesize that the long-term effects of cigarette smoke include reduction of DC maturation and function, changes that favor repeated infection, increased exacerbation frequency, and the altered (CD8(+) T-cell predominant) pattern of inflammation associated with this progressive chronic disease.     

Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity

Most humans become infected with human cytomegalovirus (HCMV). Typically, the immune system controls the infection, but the virus persists and can reactivate in states of immunodeficiency. While substantial information is available on the contribution of CD8 T cells and antibodies to anti-HCMV immunity, studies of the T_H1, T_H2, and T_H17 subsets have been limited by the low frequency of HCMV-specific CD4 T cells in peripheral blood mononuclear cell (PBMC). Using the enzyme-linked Immunospot^® assay (ELISPOT) that excels in low frequency measurements, we have established these in a sizable cohort of healthy HCMV controllers. Cytokine recall responses were seen in all seropositive donors. Specifically, interferon (IFN)-γ and/or interleukin (IL)-17 were seen in isolation or with IL-4 in all test subjects. IL-4 recall did not occur in isolation. While the ratios of T_H1, T_H2, and T_H17 cells exhibited substantial variations between different individuals these ratios and the frequencies were relatively stable when tested in samples drawn up to five years apart. IFN-γ and IL-2 co-expressing polyfunctional cells were seen in most subjects. Around half of the HCMV-specific CD4 cells were in a reversible state of exhaustion. The data provided here established the T_H1, T_H2, and T_H17 characteristic of the CD4 cells that convey immune protection for successful immune surveillance against which reactivity can be compared when the immune surveillance of HCMV fails.     

The Role of Regulatory T Cells in Respiratory Infections and Allergy and Asthma

The role of distinct CD4⁺ T-cell populations in regulating the nature and strength of immune responses is well documented and in the past has principally focused on the cross-regulation of T-helper type 1 (Th1) and Th2 cells, which secrete interferon-γ and interleukin-4, respectively. However, the identification of T cells capable of suppressing responses mediated by Th1 and Th2 cells, termed regulatory T cells (Treg cells), has prompted a paradigm shift in our understanding of the regulation of immune responses to infection and environmental antigens. This article focuses on the role of Treg cells in the lungs following infection with respiratory pathogens and discusses the targeting of Treg cells in the development of new therapies for immune-mediated respiratory diseases, such as allergy and asthma.     

Features and roles of T helper 9 cells and interleukin 9 in immunological diseases

T helper 9 (T_H9) cells are considered as newly classified helper T cells that have an important role in the regulation of immune responses. Since these cells preferentially produce IL-9, these cells are termed T_H9 cells. Recently, the role of T_H9 and its signature cytokine (IL-9) has been investigated in a wide range of diseases, including autoimmunity, allergy, infections, cancer and immunodeficiency. Herein, we review the most recent data concerning T_H9 cells and IL-9 as well as their roles in disease. These insights suggest that T_H9 cells are a future target for therapeutic intervention.     

Dendritic cells: a conductor of T cell differentiation.

Induction of different types of adaptive immune responses depending on the nature of antigens and the environmental context is crucial to cope with a variety of pathogens and concurrently to avoid pathological reaction to self antigens. Recent studies have been elucidating that the diversity of immune responses is critically controlled by dendritic cells (DCs). Two DC subsets have been identified in humans: myeloid DCs and plasmacytoid DCs. The DC subsets induce different types of adaptive immune responses depending on environmental factors. Interleukin (IL)-12 from myeloid DCs is a dominant factor for the induction of a Th1 response, whereas OX40 ligand on myeloid DCs is important for the induction of a Th2 response. Furthermore, inducible costimulator (ICOS) ligand on plasmacytoid DCs is critical for the induction of IL-10-producing regulatory T cells. Elucidating cellular and molecular mechanisms by which functions of the two DC subsets are modulated will lead to understanding the pathogenesis of various immune-related diseases and to developing novel immunological therapies.     

Dendritic cells: nature and classification.

Dendritic cells (DCs) are antigen (Ag)-presenting cells (APCs) characterized by a unique capacity to stimulate naive T cells and initiate primary immune responses. Recent studies suggest that DCs also play critical roles in the induction of central and peripheral immunological tolerance, regulate the types of T cell immune responses, and function as sentinels in innate immunity against microbes. The diverse functions of DCs in immune regulation depend on the heterogeneity of DC subsets and their functional plasticity. Here we review recent progress in our understanding of the nature and classification of DCs.     

Control of type 1 diabetes by CD4+Foxp3+ regulatory T cells: lessons from mouse models and implications for human disease

In recent years, there has been a revival of the concept of CD4⁺ regulatory T (T_reg) cells as being a central control point in various immune responses, including autoimmune responses and immunity to transplants, allergens, tumours and infectious microbes. The current literature suggests that T_reg cells are diverse in their phenotype and mechanism(s) of action, and as such, may constitute a myriad of naturally occurring and induced T cell precursors with variable degrees of regulatory potential. In this review, we summarize research from various laboratories, including our own, showing that CD4⁺Foxp3⁺ T_reg cells are critical in the control of type 1 diabetes (T1D) in mouse models and humans. In this review, we also discuss cellular and molecular determinants that impact CD4⁺Foxp3⁺ T_reg cell development and function and consequential resistance to organ‐specific autoimmune disease. Recent advances in the use of CD4⁺Foxp3⁺ T_reg cellular therapy to promote immunological tolerance in the absence of long‐term generalized immunosuppression are also presented. Copyright © 2009 John Wiley & Sons, Ltd.     

Alteration of balance between myeloid dendritic cells and plasmacytoid dendritic cells in peripheral blood of patients with asthma

Asthma, a well-known helper T cell Type 2 (Th2)-mediated disease, has a polarized immune response toward a Th2 phenotype. However, the factors causing the Th2 polarization remain to be fully determined in this disease. Dendritic cells (DCs) are the most potent antigen-presenting cells that play a central role in initiating the primary immune response. In human blood, two functional distinct subsets of DCs, myeloid DCs and plasmacytoid DCs, have been identified. Myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) are also called Type 1 DCs (DC1) and Type 2 DCs (DC2), respectively, because mDCs and pDCs were shown to preferentially differentiate naive T cells into Th1 and Th2 cells, respectively. In asthma, it can thus be speculated that an altered balance of mDCs to pDCs toward pDCs may contribute to the Th2 polarization. To clarify this, we examined the numbers of mDCs and pDCs in the peripheral blood of 44 patients with asthma and 38 normal subjects, using multicolor flow cytometry. We found that the patients with asthma had a significantly higher number of pDCs, resulting in a significant decrease in the ratio of mDCs to pDCs compared with normal subjects. These data indicate that the patients with asthma had a polarization of the mDC:pDC balance toward pDCs, which may be involved in producing the Th2-dominant immune phenotype in asthma.