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Ethan M Shevach

Publications and source records attributed to Ethan M Shevach.

At least 37 records · Page 2Linked to original sources
PubMed2004

The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells.

IL-10 reduces immunopathology in many persistent infections, yet the contribution of IL-10 from distinct cellular sources remains poorly defined. We generated IL-10/recombination-activating gene (RAG)2-deficient mice and dissected the role of T cell- and non-T cell-derived IL-10 in schistosomiasis by performing adoptive transfers. In this study, we show that IL-10 is generated by both the innate and adaptive immune response following infection, with both sources regulating the development of type-2 immunity, immune-mediated pathology, and survival of the infected host. Importantly, most of the CD4(+) T cell-produced IL-10 was confined to a subset of T cells expressing CD25. These cells were isolated from egg-induced granulomas and exhibited potent suppressive activity in vitro. Nevertheless, when naive, naturally occurring CD4(+)CD25(+) cells were depleted in adoptive transfers, recipient IL-10/RAG2-deficient animals were more susceptible than RAG2-deficient mice, confirming an additional host-protective role for non-T cell-derived IL-10. Thus, innate effectors and regulatory T cells producing IL-10 cooperate to reduce morbidity and prolong survival in schistosomiasis.

Adoptive Transfer↗
PubMed2004

Activation requirements for the induction of CD4+CD25+ T cell suppressor function.

The in vivo differentiation/survival of CD4(+)CD25(+) T suppressor cells is dependent on IL-2 and CD28-mediated costimulatory signals. To determine the cytokine and costimulatory requirements for CD25(+) T cells in vitro, we established a two-stage culture system where CD25(+) T cells were activated in a primary culture. In the subsequent culture, activated CD4(+)CD25(+) cells were then mixed with responders in order to assess their suppressor function. Pre-culture of CD25(+) T cells with anti-CD3 alone resulted in poor survival and minimal induction of suppressor activity. Pre-culture in the presence of anti-CD3 and IL-2 or IL-4, but not IL-6, IL-7, IL-9, IL-10 or IL-15, resulted in proliferation of the CD25(+) cells and induction of potent suppressor function. Inhibition of the interaction of CD28 or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with CD80/CD86 in the pre-culture of CD4(+)CD25(+) cells did not prevent the induction of suppressor function. Furthermore, the inhibition of costimulatory signals did not inhibit the ability of fresh CD25(+) T cells to inhibit CD8(+) responders under conditions where activation of the responders was independent of CD80/CD86. These studies support the view that activation of CD25(+) T cells requires IL-2/IL-4 for their survival/differentiation into effector cells, but is independent of CD28/CTLA-4-mediated costimulation.

Animals↗
PubMed2004

A novel protective model against experimental allergic encephalomyelitis in mice expressing a transgenic TCR-specific for myelin oligodendrocyte glycoprotein.

Myelin oligodendrocyte glycoprotein (MOG) is an important autoantigen in multiple sclerosis and in experimental autoimmune encephalomyelitis (EAE). We generated a T cell receptor (TCR) transgenic (Tg) mouse expressing a TCR derived from an encephalitogenic T cell clone specific for MOG(35-55). This mouse failed to develop EAE spontaneously and developed mild EAE at late onset when immunized with MOG(35-55). The Tg T cells produced large amounts of IL-4 when stimulated with MOG(35-55) and underwent FAS/FAS-L-mediated activation-induced cell death when stimulated with MOG(35-55) and IL-12. The unique phenotype of these autoantigen-specific T cells may represent an important mechanism of protection against autoimmune disease.

Animals↗
PubMed2004

Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance.

Self/non-self discrimination is a complex process that involves maintaining tolerance to autoantigens while preserving the potential to generate an effective humoral and cellular immune responses against invading pathogens. In the last decade, there has been a remarkable resurgence in research on suppressor or regulatory T cells. Few areas have captivated the attention of immunologists so vividly and entertained so many passionate debates. Indeed, CD4(+)CD25(+) Treg, which are at the very center of this fascination, have emerged as a dominant T cell population capable of mediating peripheral tolerance to autoantigens, but whose functions have now been extended to regulation of T cell responses directed to foreign antigens. However, a number of fundamental questions concerning the origin, phenotypic nature and mechanism of action of CD4(+)CD25(+) Treg cells remain elusive and misunderstood. We propose the existence of two general subsets of CD4(+)CD25(+) Treg cells, naturally-occurring and induced, that differ in their origin, developmental and activation requirements, and mechanism of action.

Animals↗
PubMed2004

Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy.

Regulatory T cells play an important role in the maintenance of immunological self-tolerance by suppressing immune responses against autoimmune diseases and cancer. Little is known, however, about the nature of the physiological target antigens for CD4(+) regulatory T (Treg) cells. Here we report the identification of the LAGE1 protein as a ligand for tumor-specific CD4(+) Treg cell clones generated from the tumor-infiltrating lymphocytes (TILs) of cancer patients. Phenotypic and functional analyses demonstrated that they were antigen-specific CD4(+) Treg cells expressing CD25 and GITR molecules and possessing suppressive activity on the proliferative response of naive CD4(+) T cells to anti-CD3 antibody stimulation. Ligand-specific activation and cell-cell contact were required for TIL102 Treg cells to exert suppressive activity on CD4(+) effector cells. These findings suggest that the presence of tumor-specific CD4(+) Treg cells at tumor sites may have a profound effect on the inhibition of T cell responses against cancer.

Antigens, Neoplasm↗
PubMed2003

Control of T cell activation by CD4+CD25+ suppressor T cells.

Although the concept of a separate lineage of T cells specifically equipped to suppress immune responses was initially proposed more than 30 years ago, progress in this area of immunoregulation has been hampered by the lack of solid biochemical and molecular data to support the existence of the soluble products of these purported suppressor T cells. Studies over the past 5-10 years have identified a distinct lineage of CD4+CD25+ regulatory or suppressor T cells that control autoreactive effector cells and prevent autoimmunity. The mechanism by which CD4+CD25+ T cells inhibit T cell activation in vivo or in vitro is still poorly defined. While autoreactive effector T cells undergo massive proliferation and expansion following injection into immunocompromised recipients, CD4+CD25+ T cells do not inhibit this lymphopaenia-induced proliferation and act later in the activation process at the site of immune damage in the target organ. The development of in vitro models that partially mimic the in vivo properties of the CD4+CD25+ regulatory T cells has facilitated their characterization. A member of the tumour necrosis receptor family, the GITR is expressed on CD4+CD25+ T cells and after interaction with its ligand down-regulates suppressor activity. Multiple methods of manipulating both the numbers of CD4+CD25+ suppressor T cells and their activation status are now available and will rapidly be applied to therapy of autoimmune, infectious and malignant diseases.

Animals↗
PubMed2002

CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.

The long-term persistence of pathogens in a host that is also able to maintain strong resistance to reinfection, referred to as concomitant immunity, is a hallmark of certain infectious diseases, including tuberculosis and leishmaniasis. The ability of pathogens to establish latency in immune individuals often has severe consequences for disease reactivation. Here we show that the persistence of Leishmania major in the skin after healing in resistant C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T cells. These cells constitute 5-10% of peripheral CD4+ T cells in naive mice and humans, and suppress several potentially pathogenic responses in vivo, particularly T-cell responses directed against self-antigens. During infection by L. major, CD4+CD25+ T cells accumulate in the dermis, where they suppress-by both interleukin-10-dependent and interleukin-10-independent mechanisms-the ability of CD4+CD25- effector T cells to eliminate the parasite from the site. The sterilizing immunity achieved in mice with impaired IL-10 activity is followed by the loss of immunity to reinfection, indicating that the equilibrium established between effector and regulatory T cells in sites of chronic infection might reflect both parasite and host survival strategies.

Animals↗
PubMed2002

Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node.

The major histocompatibility complex (MHC)-dependent presentation of processed tissue-specific self-antigens can contribute to either peripheral (extrathymic) tolerance or the differentiation of autoreactive T cells. Here, we have studied the MHC class II molecule presentation of gastric parietal cell (PC)-specific H(+)/K(+)-ATPase, which induces a destructive autoimmune gastritis in BALB/c mice lacking CD4(+) CD25(+) regulatory T cells. Immunofluorescence microscopy showed physical association of CD11c(+) dendritic cells (DCs) with PCs in the gastric mucosa. H(+)/K(+)-ATPase protein was found within vesicular compartments of a few CD11c(+) DCs only in the draining gastric lymph node (LN) and these antigen-containing DCs increased markedly in number with the onset of tissue destruction in autoimmune animals. Both CD8alpha(hi) and CD8alpha(lo) gastric DCs, but not peripheral or mesenteric DCs, showed evidence of constitutive in vivo processing and presentation of H(+)/K(+)-ATPase. These data provide direct support for a widely held model of local tissue antigen uptake and trafficking by DCs in normal animals and demonstrate that DCs in the draining LN can present a tissue-specific self-antigen under noninflammatory conditions without fully deleting autoreactive T cells or inducing active autoimmunity.

Animals↗
PubMed2002

CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness.

CD4(+)CD25(+) regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4(+)CD25(-) T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact-dependent and cytokine independent. The role of TGF-beta1 in CD4(+)CD25(+) suppressor function remains unclear. While most studies have failed to reverse suppression with anti-transforming growth factor (TGF)-beta1 in vitro, one recent study has reported that CD4(+)CD25(+) T cells express cell surface TGF-beta1 and that suppression can be completely abrogated by high concentrations of anti-TGF-beta suggesting that cell-associated TGF-beta1 was the primary effector of CD4(+)CD25(+)-mediated suppression. Here, we have reevaluated the role of TGF-beta1 in CD4(+)CD25(+)-mediated suppression. Neutralization of TGF-beta1 with either monoclonal antibody (mAb) or soluble TGF-betaRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4(+)CD25(+) T cells. Responder T cells from Smad3(-/-) or dominant-negative TGF-beta type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-beta1-induced growth arrest, were as susceptible to CD4(+)CD25(+)-mediated suppression as T cells from wild-type mice. Furthermore, CD4(+)CD25(+) T cells from neonatal TGF-beta1(-/-) mice were as suppressive as CD4(+)CD25(+) from TGF-beta1(+/+) mice. Collectively, these results demonstrate that CD4(+)CD25(+) suppressor function can occur independently of TGF-beta1.

Animals↗
PubMed2002

Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease.

Thymectomy of BALB/c mice on day 3 of life results in the development of autoimmune gastritis (AIG) due to the absence of CD4(+)CD25(+) regulatory T cells. However, depletion of CD4(+)CD25(+) T cells by treatment with anti-CD25 rarely resulted in AIG. Depletion was efficient, as transfer of splenocytes from depleted mice induced AIG in nu/nu mice. One explanation for this result is that CD4(+)CD25(-) T cells upon transfer to nude recipients undergo lymphopenia-induced proliferation, providing a signal for T cell activation. Cotransfer of CD25(+) T cells did not inhibit initial proliferation but did suppress AIG. Surprisingly, immunization with the AIG target Ag, H/K ATPase, in IFA failed to induce disease in normal animals but induced severe AIG in CD25-depleted mice. These results demonstrate that second signals (nonspecific proliferation, TCR activation, or inflammation) are needed for induction of autoimmunity in the absence of CD25(+) regulatory T cells.

Animals↗
PubMed2002

Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression.

Two key events occur during the differentiation of IFN-gamma-secreting Th1 cells: up-regulation of IL-12Rbeta2 and IL-12-driven up-regulation of IL-18Ralpha. We previously demonstrated that IL-12-driven up-regulation of IL-18Ralpha expression is severely impaired in IFN-gamma(-/-) mice. However, it was unclear from these studies how IFN-gamma influenced IL-18Ralpha since IFN-gamma alone had no direct effect on IL-18Ralpha expression. In the absence of IL-4, IL-12-dependent up-regulation of IL-18Ralpha/IL-12Rbeta2 was independent of IFN-gamma. However, in the presence of IL-4, IFN-gamma functions to limit the negative effects of IL-4 on both IL-18Ralpha and IL-12Rbeta2. Neutralization of IL-4 restored IL-12-driven up-regulation of IL-18Ralpha/IL-12Rbeta2 in an IFN-gamma-independent fashion. In the absence of both IL-12 and IL-4, IFN-gamma up-regulates IL-12beta2 expression and primes IFN-gamma-producing Th1 cells. When T cells were primed in the presence of IL-4, no correlation was found between the levels of expression of the IL-18Ralpha or the IL-12Rbeta2 and the capacity of these cells to produce IFN-gamma, suggesting that IL-4 may also negatively affect IL-12-mediated signal transduction and thus Th1 differentiation. These data clarify the role of IFN-gamma in regulation of IL-18Ralpha/IL-12Rbeta2 during both IL-12-dependent and IL-12-independent Th1 differentiation.

Adjuvants, Immunologic↗
PubMed2002

Cutting Edge: IL-10-producing CD4+ T cells mediate tumor rejection.

IL-10 has potent immunosuppressive properties, and IL-10-producing CD4+ Tr1 cells have been characterized as regulators of Th1-mediated immunity. In this study, using a s.c. model of glioma cell growth in mice, we demonstrate that CD4+, but not CD8+, T cells play a critical role in tumor rejection following vaccination with irradiated glioma cells. Surprisingly, glioma-specific CD4+ T cells produce IL-10 but neither IL-4 nor IFN-gamma, and glioma rejection is compromised in IL-10(-/-) hosts. Hence, our findings demonstrate that IL-10-producing CD4+ T cells can manifest antitumor functions and suggest that IL-10 may have proinflammatory effects in disease states.

Animals↗
PubMed2002

The IL-10-producing competence of Th2 cells generated in vitro is IL-4 dependent.

Previous studies have suggested that activation of CD4+ T cells in the presence of IL-10 results in the generation of a population of T cells, T regulatory 1 (Tr1) cells, that primarily produce IL-10 and TGF-beta, but not IL-4. The relationship between Tr1 cells and conventional Th2 cells remains unclear. We were not successful in our attempts to generate significant numbers of antigen-specific T cells that secreted IL-10, but not IL-4, by culture in the presence of IL-10. The small numbers of cells that produced IL-10 only were completely dependent on the presence of IL-4 for their generation. In a polyclonal model, the development of IL-10 only producers was completely dependent on the presence of signal transducer and activator of transcription 6. Studies with myelin basic protein-specific T cells derived from an IL-4-deficient mouse confirmed the absolute requirement for IL-4 for the generation of IL-10 producers under all culture conditions. These IL-10-producing Th2 cells failed to inhibit EAE in an adoptive transfer model and were pathogenic when transferred to immunodeficient mice. Collectively, our results raise doubts about the existence of a unique population of CD4+ regulatory T cells that can be generated by activation in the presence of IL-10.

Animals↗
PubMed2002

Differentiated Th1 autoreactive effector cells can induce experimental autoimmune encephalomyelitis in the absence of IL-12 and CD40/CD40L interactions.

IL-12 plays a critical role in the priming of Th1 responses to bacterial/parasitic antigens and autoantigens. Several studies have demonstrated a dependency on CD40/CD40L interactions and IL-12 for maintenance of both antibacterial/parasitic and autoreactive Th1 cells in vivo. However, it is still unclear if fully differentiated Th1 effectors require continued stimulation by IL-12. We demonstrate that the proliferative response and IFN-gamma production by a fully differentiated T cell line specific for myelin oligodendrocyte glycoprotein are completely independent of IL-12 and CD40/CD40L interactions. The capacity of this line to adoptively transfer experimental autoimmune encephalomyelitis is also independent of IL-12 and CD40/CD40L. These results have important implications regarding the therapeutic usefulness of blockade of IL-12 or the CD40/CD40L pathway for treatment of autoimmune disease.

Adoptive Transfer↗
PubMed2002

CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor.

CD4(+)CD25(+) immunoregulatory T cells represent a unique lineage of thymic-derived cells that potently suppress both in vitro and in vivo effector T cell function. We analyzed CD4(+)CD25(+) and CD4(+)CD25(-) T cells by DNA microarray, identifying 29 genes differentially expressed in the resting subpopulations, and 77 that were differentially expressed following activation. Most of these genes were elevated in the CD4(+)CD25(+) population, suggesting a previously activated phenotype. Among these were a number of genes that antagonize signaling, including members of the SOCS family, which may contribute to their anergic phenotype. Multiple cell surface receptors also had increased expression in CD4(+)CD25(+) cells, including GITR, a member of the TNF receptor superfamily. Importantly, antibodies to GITR abrogated suppression, demonstrating a functional role for this receptor in regulating the CD4(+)CD25(+) T cell subset.

Animals↗
PubMed2002

CD4+ CD25+ suppressor T cells: more questions than answers.

Several mechanisms control discrimination between self and non-self, including the thymic deletion of autoreactive T cells and the induction of anergy in the periphery. In addition to these passive mechanisms, evidence has accumulated for the active suppression of autoreactivity by a population of regulatory or suppressor T cells that co-express CD4 and CD25 (the interleukin-2 receptor alpha-chain). CD4+ CD25+ T cells are powerful inhibitors of T-cell activation both in vivo and in vitro. The enhancement of suppressor-cell function might prove useful for the treatment of immune-mediated diseases, whereas the downregulation of these cells might be beneficial for the enhancement of the immunogenicity of vaccines that are specific for tumour antigens.

Abatacept↗