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H Groux

Publications and source records attributed to H Groux.

At least 19 recordsLinked to original sources
PubMed2001

Differentiation of regulatory T cells 1 is induced by CD2 costimulation.

Induction and maintenance of peripheral tolerance is an important phenomenon for the control of homeostasis in the immune system. There is now compelling evidence for CD4(+) T cells that prevent immune pathology, both in autoimmunity and in transplantation. However, the mechanisms involved in the specific differentiation of these T cells are unknown. We had previously shown that repetitive stimulations of naive T cells in the presence of IL-10 induce the differentiation of T regulatory cells 1. We further dissected the mechanism of IL-10 function and demonstrated that IL-10 acts by the down-regulation of most costimulatory molecules without modifying the expression of CD58. Using artificial APCs expressing various costimulatory molecules, we demonstrated that, in contrast to other costimulation patterns, costimulation via CD2 alone, in the absence of costimulations through CD28- or LFA-1, induced T cell anergy in an IL-10-independent pathway along with the differentiation of Ag-specific regulatory T cells. T regulatory cell-1 differentiation via CD2 was very efficient as both high IL-10 secretion and regulatory function were observed after the first stimulation of naive T cells with CD32-CD58 L cells. The possibility to rapidly induce the differentiation of Ag-specific regulatory T cells will certainly accelerate their characterization and their potential use as regulators of T cell-mediated diseases.

Animals↗
PubMed2001

Regulation of TGF-beta response during T cell activation is modulated by IL-10.

TGF-beta1 is an important pleiotropic cytokine that has been described to have both stimulatory and inhibitory effects on cell growth and differentiation. For several cell types, the effect of TGF-beta1 was found to correlate with the differentiation stage of the cells and the presence of other cytokines. In this report, we address the influence of TGF-beta1 on CD4(+) T cell activation by evaluating the effect of TGF-beta1 on the proliferative and cytokine responses of purified resting and activated human or mouse CD4(+) T cells. TGF-beta1 inhibits proliferation and cytokine secretion on resting CD4(+) T cells but has no inhibitory effect on activated T cells. Moreover, TGF-beta1 unresponsiveness of activated T cells was correlated with a down-regulation in the expression of the TGF-beta receptor type II. Interestingly, IL-10 addition enhances TGF-beta receptor type II expression and restores TGF-beta responsiveness on activated T cells. These results indicated that TGF-beta responsiveness is sequentially regulated on T cells by the modulation of the of TGF-beta receptor type II chain expression. Moreover, we have identified a novel regulatory role of IL-10 on TGF-beta-dependent T cell growth that can explain the control of T cell activation on chronic vs acute inflammatory sites.

Adjuvants, Immunologic↗
PubMed2001

An overview of regulatory T cells.

The induction of tolerance is essential for the maintenance of immune homeostasis and for the prevention of autoimmune diseases. To induce tolerance the immune system uses several mechanisms, including the deletion of autoreactive T cells, the induction of anergy and active suppression of autoimmune responses. The mechanisms of thymic deletion and anergy of autoreactive T cells are well characterized, whereas active suppression by T regulatory cells, which has recently emerged as an essential component of the immune response to induce peripheral tolerance, is less well understood. Results from seminal studies by a number of laboratories have renewed interest in (CD4(+)) T cells with regulatory properties and some of the researchers who have been involved in this effort have contributed to this Forum on regulatory T cells. This general overview on regulatory T cells comments on recent results in the field of regulatory T cells and presents our current knowledge on Tr1 T cells.

Animals↗
PubMed2000

T regulatory cells 1 inhibit a Th2-specific response in vivo.

We recently described a new population of CD4(+) regulatory T cells (Tr1) that inhibits proliferative responses of bystander T cells and prevents colitis induction in vivo through the secretion of IL-10. IL-10, which had been primarily described as a Th2-specific cytokine inhibiting Th1 responses, has displayed in several models a more general immune suppression on both types of effector T cell responses. Using an immediate hypersensitivity model in which BALB/c mice immunized with OVA (alum) normally generate Th2-dominated responses, we examined the ability of OVA-specific Tr1 T cell clones to inhibit OVA-specific cytokines and Ab responses. In contrast to Th2 or Th1 T cell clones, transfer of Tr1 T cell clones coincident with OVA immunization inhibited Ag-specific serum IgE responses, whereas IgG1 and IgG2a synthesis were not affected. This specific inhibition was mediated in part through IL-10 secretion as anti-IL-10 receptor Abs treatment reverted the inhibitory effect of Tr1 T cell clones. Although specifically targeted to IgE responses, Tr1 clones' inhibitory effects were more profound as they affected Ag-specific Th2 cell priming both in term of proliferative responses and cytokine secretion. These results suggest that regulatory T cells may play a fundamental role in maintaining the balance of the immune system to prevent allergic disorders.

Adoptive Transfer↗
PubMed2000

Characterization of T cell subpopulations involved in the pathogenesis of asthma and allergic diseases.

Allergic asthma is a complex and heterogeneous disease which is characterized by intermittent reversible airway obstruction, chronic inflammation of the airways, bronchial hyperreactivity and an infiltration of lymphocytes and eosinophils into the airway submucosa. Animal models and clinical studies in humans have indicated an important role for T helper type 2 lymphocytes, producing IL-4, IL-5 and IL-13, in the pathogenesis of this disorder. However, although IL-4 and IL-13 have strong anti-inflammatory properties, the physiologic anti-inflammatory Th2 response does not seem to be operational in allergic asthma. Moreover, the induction of a Th1 response seems to aggravate, rather than ameliorate, its inflammatory character. This article will focus on the involvement of T lymphocyte subpopulations in the pathogenesis of allergic asthma and allergic diseases. In addition, a potential role of the subpopulation(s) of T regulatory cells in the induction and/or maintaince of the disease process will be discussed.

Animals↗
PubMed2000

Can interleukin-10 be used as a true immunoregulatory cytokine?

Interleukin-10 (IL-10) is a cytokine that is currently regarded as a potential therapy for inflammatory diseases involving T helper 1-type responses because of its ability to downregulate several major functions of Th1 cells and macrophages. There are also evidence that IL-10 could be useful in controlling Th2-mediated inflammatory processes. However IL-10 has also immunostimulatory properties especially on B-cells and activated CD8+ T cells. These pleiotropic effects may explain the discrepancy observed after IL-10 treatment in different in vivo experimental models. We have recently shown that IL-10 induces the differentiation of a subset of regulatory CD4+ T cells (Tr1). In different in vivo models, these cells were shown to inhibit Th1 and Th2-type inflammatory responses through the secretion of IL-10. These Tr1 cells may thus be used in specific cellular therapy in order to deliver IL-10 precisely at the site of inflammation.

Adjuvants, Immunologic↗
PubMed1999

IL-10 transgenic mice present a defect in T cell development reminiscent of SCID patients.

To analyze the effect of IL-10 overexpressed by APCs as observed in some SCID patients, we have expressed the human IL-10 cDNA under the control of the murine MHC class II promoter in transgenic mice. Similar to SCID patients, these mice presented a defect in T cell maturation characterized by a rapid thymic aplasia that started after birth. The blockage in T cell maturation was strictly restricted to TCR-alpha beta T cells as the absolute number of thymic dendritic, TCR-gamma delta and NK1.1 T cells were equivalent to control littermates. Crossing IL-10 transgenic mice with TCR transgenic mice or treatment with staphylococcal enterotoxin B showed that the defect was not related to the impairment of positive or negative selection. However, repopulating of IL-10 transgenic mouse-fetal thymic organ culture with different stages of triple negative T cells isolated from control mice showed that the blockage occurred specifically at the pre-T cell stage and was reverted by treatment with blocking anti-IL-10 mAbs. These results demonstrate that IL-10 regulates T cell maturation and that dysregulation of IL-10 expression can lead to severe T cell immunodeficiency.

Animals↗
PubMed1999

Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis.

The effectiveness of interleukin 10 (IL-10) in the treatment of autoimmune-mediated central nervous system inflammation is controversial. Studies of the model system, experimental autoimmune encephalomyelitis (EAE), using various routes, regimens, and delivery methods of IL-10 suggest that these variables may affect its immunoregulatory function. To study the influence of these factors on IL-10 regulation of EAE pathogenesis, we have analyzed transgenic mice expressing human IL-10 (hIL-10) transgene under the control of a class II major histocompatibility complex (MHC) promoter. The hIL-10 transgenic mice are highly resistant to EAE induced by active immunization, and this resistance appears to be mediated by suppression of autoreactive T cell function. Myelin-reactive T helper 1 cells are induced but nonpathogenic in the IL-10 transgenic mice. Antibody depletion confirmed that EAE resistance is dependent on the presence of the transgenic IL-10. Mice expressing the hIL-10 transgene but not the endogenous murine IL-10 gene demonstrated that transgenic IL-10 from MHC class II-expressing cells is sufficient to block induction of EAE. This study demonstrates that IL-10 can prevent EAE completely if present at appropriate levels and times during disease induction.

Animals↗
PubMed1999

A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells.

IL-10 is a cytokine secreted by a wide variety of cells type that has pleiotropic stimulatory and suppressive activities on both lymphoid and myeloid cells in vitro. To analyze the consequences of high IL-10 secretion by APCs in immune responses, we produced transgenic mice expressing human IL-10 directed by the MHC class II Ea promoter. Despite alterations in the development of T and B cells, no gross abnormalities were detected in peripheral lymphocyte populations or serum Ig levels. However, when immunized using conditions that give either a Th2-type or a Th1-type response, IL-10 transgenic mice failed to mount a significant T or B cell immune response to OVA. IL-10 transgenic mice were also highly susceptible to infection with intracellular pathogens like Listeria monocytogenes or Leishmania major, in contrast to IL-10 transgenic mice, where the transgene was express in T cells. Finally, the recently described stimulatory effect of IL-10 on CD8+ T cells was confirmed by the ability of IL-10 transgenic mice to limit the growth of immunogenic tumors by a CTL-mediated mechanism. These results demonstrate, that, depending on the type of immune response, IL-10 can mediate immunosuppressive or immunostimulatory activities in vivo.

Animals↗
PubMed1999

Regulatory T cells and inflammatory bowel disease.

Recent studies have identified interleukin 10 as a differentiation factor for a novel subset of immune suppressive regulatory T cells. Here, Hervé Groux and Fiona Powrie discuss the role that these cells play in the regulation of immune responses to enteric antigens and suggest that a deficiency in these cells might be involved in the pathogenesis of inflammatory bowel disease.

Animals↗
PubMed1998

Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells.

IL-10 is a well-documented immunosuppressant that inhibits macrophage-dependent Ag presentation and CD4+ T cell proliferation in vitro. We report that IL-10 inhibits alloantigen-specific proliferative responses and induces a long lasting anergic state in human purified CD8+ T cells when added concomitantly with the Ag in the presence of APC. Moreover, the generation of allospecific cytotoxic activity is inhibited by IL-10. These effects are indirect and are mediated through inhibition of the costimulatory functions of APC. In contrast, IL-10 has no direct inhibitory effects on the proliferation of purified CD8+ T cells activated by anti-CD3 mAb and promotes the growth of activated CD8+ T cells in combination with low doses of IL-2. Taken together, these results indicate that IL-10 has differential effects on CD8+ T cells depending on their state of activation, which may explain both the enhancing and inhibitory effects observed after IL-10 treatment in different in vivo experimental models.

Antigens, CD↗
PubMed1997

A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis.

Induction and maintenance of peripheral tolerance are important mechanisms to maintain the balance of the immune system. In addition to the deletion of T cells and their failure to respond in certain circumstances, active suppression mediated by T cells or T-cell factors has been proposed as a mechanism for maintaining peripheral tolerance. However, the inability to isolate and clone regulatory T cells involved in antigen-specific inhibition of immune responses has made it difficult to understand the mechanisms underlying such active suppression. Here we show that chronic activation of both human and murine CD4+ T cells in the presence of interleukin (IL)-10 gives rise to CD4+ T-cell clones with low proliferative capacity, producing high levels of IL-10, low levels of IL-2 and no IL-4. These antigen-specific T-cell clones suppress the proliferation of CD4+ T cells in response to antigen, and prevent colitis induced in SCID mice by pathogenic CD4+CD45RB(high) splenic T cells. Thus IL-10 drives the generation of a CD4+ T-cell subset, designated T regulatory cells 1 (Tr1), which suppresses antigen-specific immune responses and actively downregulates a pathological immune response in vivo.

Animals↗
PubMed1997

Induction of human T helper cell type 1 differentiation results in loss of IFN-gamma receptor beta-chain expression.

Differential expression of cytokine receptors accounts for an important regulatory mechanism in differentiation of Th1/Th2 subsets. Here, we report that human Th0 and Th2 clones constitutively express transcripts for the IFN-gammaR beta-chain, whereas mRNA for this signaling component of the IFN-gamma receptor is absent in Th1 clones. Activation of T cell clones, however, resulted in a transient induction or enhancement of IFN-gammaR beta-chain mRNA expression in Th1 clones and Th0/Th2 clones, respectively. IL-12-mediated Th1 cell differentiation of naive CD4+, CD45RA+ cord blood T cells, which constitutively express IFN-gammaR beta-chain mRNA, resulted in a loss of expression of this cytokine receptor chain after 6 to 12 days of culture. In contrast, Th2 populations, differentiated from CD4+, CD45RA+ cord blood T cells in the presence of IL-4, continued to express high levels of IFN-gammaR beta-chain transcripts. The loss of IFN-gammaR beta-chain expression in Th1 populations was accompanied by a failure of IFN-gamma to induce the expression of the IFN-gamma-inducible gene, IFN response factor-1, whereas IFN-gamma was effective in inducing IFN response factor-1 mRNA expression in Th0 and Th2 cells. These results indicate that down-regulation of the IFN-gammaR beta-chain correlates with impaired IFN-gamma-induced signaling in Th1 cells. Finally, Th2 populations, generated in the presence of both IL-4 and IFN-gamma, expressed levels of IFN-gammaR beta-chain transcripts similar to those produced by cells differentiated in the presence of IL-4 only, demonstrating that IFN-gamma does not modulate the expression of its receptor. Together, these data indicate that human Th0/Th2 and Th1 subsets, respectively, can be distinguished based on the expression of the IFN-gammaR beta-chain.

CD4-Positive T-Lymphocytes↗
PubMed1997

Isolation and characterization of transformed human T-cell lines infected by Epstein-Barr virus.

Epstein-Barr virus (EBV) is a human lymphotropic virus whose main targets have traditionally been described as B lymphocytes and epithelial cells. Here we report the isolation and characterization of largely monoclonal transformed human T-cell lines infected by EBV. The transformed T cells expressed CD2, CD3, and either CD4 or CD8 surface molecules and more generally displayed the phenotype of naive T cells with a complete and clonal rearrangement of the T-cell receptor. None of the cell lines expressed B cells, natural killer, or myeloid antigens or had immunoglobulins genes rearrangement. They grew in the absence of growth factor; however, they all secreted interleukin-2 after mitogenic activation. Polymerase chain reaction (PCR) analysis showed the presence of EBV DNA in all these cell lines. Moreover, Southern blot analysis of one of these cell lines shows the presence of circular episomic EBV DNA, and by Northern blot or reverse transcriptase-PCR analysis, only the expression of Epstein-Barr nuclear antigen-1 (EBNA-1) and latent membrane protein-1 (LMP-1) genes was detected. Finally, the complete transformed phenotype of this T-cell line was shown by its injection into nude or recombination activating gene 2 (RAG2)-deficient mice that led to the formation of solid tumors.

Animals↗
PubMed1997

Priming of human CD4+ antigen-specific T cells to undergo apoptosis by HIV-infected monocytes. A two-step mechanism involving the gp120 molecule.

The study of the pathology of HIV-1 infection in chimpanzees supports the idea of the crucial role of HIV-infected monocytes in the pathogenesis of AIDS, although viral mechanisms that lead to T cell dysfunction and deletion during HIV infection are still unclear. We show here that HIV-1-infected antigen-presenting monocytes (APCs) are able to prime in vitro non-HIV-infected antigen-specific CD4+ T cell lines or peripheral blood CD4+ T cells to undergo apoptosis after antigen-specific restimulation. The priming of T cells for apoptosis occurs in the absence of HIV replication in the T cells. Priming for apoptosis required two concomitant signals present on the same APC, an antigenic stimulus and a second signal provided by the HIV gp120 protein as demonstrated by the use as APCs of EBV-LCLs infected with different recombinant deleted proviruses or transfected with different HIV proteins. These results provide a mechanism for the priming for apoptosis of T cells in HIV-infected patients, implicating a role for HIV-infected APCs in the induction of T cell dysfunction and depletion in AIDS.

Antigen-Presenting Cells↗
PubMed1996

Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells.

Human CD4+ T cells, activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous interleukin (IL) 10, specifically failed to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness could be induced by activation of CD4+ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. The anergic T cells failed to produce IL-2, IL-5, IL-10, interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state was long-lasting. T cell anergy could not be reversed after restimulation of the cells with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression was normal. In addition, restimulation of anergized T cells with anti-CD3 mAbs induced normal Ca2+ fluxes and resulted in increased CD3, CD28, and class II major histocompatibility complex expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor alpha chain was not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts showed comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca2+ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. Taken together, these data demonstrate that IL-10 induces T cell anergy and therefore may play an important role in the induction and maintenance of antigen-specific T cell tolerance.

CD28 Antigens↗
PubMed1996

Selective CD4+ T cell deletion after specific activation in HIV-infected individuals; protection by anti-CD28 monoclonal antibodies.

AIDS is characterized by a progressive decline in the number of CD4+ T cells. This is preceded by an early selective defect in the proliferation of these cells to recall antigens [1-3], pokeweed mitogen (PWM) [4-6] and to superantigens (SAg) [4,7]. In contrast, the proliferative response to phytohaemagglutinin (PHA) remains intact [1,2,5]. We and others have shown that the proliferative defect in response to some stimuli was in fact due to the induction of cell death [4,7]. The activation-induced cell death mechanism that explains the proliferative defects observed in vitro might also account for the progressive in vivo deletion of CD4+ T cells. Indeed, studies performed on different models of primates have shown that induction of cell death in CD4+ T cells was detected only when T cells were isolated from animals infected with a type of retrovirus that induces an AIDS-like disease [8]. This correlation prompted us to analyse further the mechanism of HIV-induced activation cell death to determine the specificity and rate of induction of cell death. T cells from HIV-infected individuals were activated with superantigens and the V beta T cell receptor (TCR) expression analysed. Data presented here show that cell death is restricted to activated CD4+ T cells, and does not affect bystander cells. More importantly, addition of anti-CD28 MoAb specifically inhibited the induction of apoptosis, raising possibilities for therapy.

Antibodies, Monoclonal↗