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1.
Nat Immunol ; 9(1): 42-53, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18037890

RESUMO

Although much is known about the migration of T cells from blood to lymph nodes, less is known about the mechanisms regulating the migration of T cells from tissues into lymph nodes through afferent lymphatics. Here we investigated T cell egress from nonlymphoid tissues into afferent lymph in vivo and developed an experimental model to recapitulate this process in vitro. Agonism of sphingosine 1-phosphate receptor 1 inhibited the entry of tissue T cells into afferent lymphatics in homeostatic and inflammatory conditions and caused the arrest, mediated at least partially by interactions of the integrin LFA-1 with its ligand ICAM-1 and of the integrin VLA-4 with its ligand VCAM-1, of polarized T cells at the basal surface of lymphatic but not blood vessel endothelium. Thus, the increased sphingosine 1-phosphate present in inflamed peripheral tissues may induce T cell retention and suppress T cell egress.


Assuntos
Vasos Linfáticos/imunologia , Lisofosfolipídeos/metabolismo , Modelos Imunológicos , Receptores de Lisoesfingolipídeo/imunologia , Esfingosina/análogos & derivados , Linfócitos T/imunologia , Animais , Movimento Celular , Endotélio Linfático/imunologia , Cloridrato de Fingolimode , Homeostase , Inflamação/imunologia , Integrina alfa4beta1/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Linfonodos/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Propilenoglicóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Transdução de Sinais , Esfingosina/metabolismo , Esfingosina/farmacologia , Molécula 1 de Adesão de Célula Vascular/imunologia
2.
Immunity ; 30(3): 458-69, 2009 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-19303390

RESUMO

To determine the site and mechanism of suppression by regulatory T (Treg) cells, we investigated their migration and function in an islet allograft model. Treg cells first migrated from blood to the inflamed allograft where they were essential for the suppression of alloimmunity. This process was dependent on the chemokine receptors CCR2, CCR4, and CCR5 and P- and E-selectin ligands. In the allograft, Treg cells were activated and subsequently migrated to the draining lymph nodes (dLNs) in a CCR2, CCR5, and CCR7 fashion; this movement was essential for optimal suppression. Treg cells inhibited dendritic cell migration in a TGF-beta and IL-10 dependent fashion and suppressed antigen-specific T effector cell migration, accumulation, and proliferation in dLNs and allografts. These results showed that sequential migration from blood to the target tissue and to dLNs is required for Treg cells to differentiate and execute fully their suppressive function.


Assuntos
Autoimunidade/imunologia , Movimento Celular/imunologia , Linfonodos/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Inflamação , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Hepatology ; 62(1): 279-91, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25810240

RESUMO

UNLABELLED: The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against particle-bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune-mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low-dose peptide antigens coupled to inert particles, immunological readouts, and sophisticated intravital multiphoton microscopy-based imaging of liver in mice. We show that liver resident macrophages, Kupffer cells (KCs), but not hepatic monocyte-derived macrophages or dendritic cells (DCs), are the central cellular scavenger for circulating particle-associated antigens in homeostasis. KC-associated antigen presentation induces CD4 T-cell arrest, expansion of naturally occurring Foxp3(+) CD25(+) interleukin-10-producing antigen-specific regulatory T cells (Tregs) and tolerogenic immunity. Particle-associated tolerance induction in the liver protected mice from kidney inflammation in T-cell-mediated glomerulonephritis, indicating therapeutic potential of targeting KC for immune-mediated extrahepatic disorders. Liver inflammation in two independent experimental models of chronic liver injury and fibrosis abrogated tolerance induction and led to an immunogenic reprogramming of antigen-specific CD4 T cells. In injured liver, infiltrating monocyte-derived macrophages largely augment the hepatic phagocyte compartment, resulting in antigen redistribution between myeloid cell populations and, simultaneously, KCs lose signature markers of their tolerogenic phenotype. CONCLUSIONS: Hepatic induction of tissue-protective immunological tolerance against particulate antigens is dependent on KCs as well as on a noninflamed liver microenvironment, thereby providing mechanistic explanations for the clinical observation of immune dysfunction and tolerance break in patients with advanced liver diseases.


Assuntos
Tolerância Imunológica , Células de Kupffer/fisiologia , Fígado/imunologia , Animais , Apresentação de Antígeno , Antígenos , Proliferação de Células , Camundongos Endogâmicos C57BL , Linfócitos T/fisiologia
4.
J Immunol ; 182(10): 6226-36, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19414776

RESUMO

IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double-deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and it induced Stat1-independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6-deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE (Maf recognition element) motif in the IL-10 promoter. Taken together, these data reveal a novel role for c-Maf in regulating T effector development, and they suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-10/biossíntese , Proteínas Proto-Oncogênicas c-maf/imunologia , Subpopulações de Linfócitos T/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Western Blotting , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Expressão Gênica , Interleucina-10/imunologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-maf/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Fator de Crescimento Transformador beta/metabolismo
5.
Curr Opin Organ Transplant ; 15(4): 416-21, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20616727

RESUMO

PURPOSE OF REVIEW: Understanding the interplay between myeloid dendritic cells and T cells under tolerogenic conditions, and whether their interactions induce the development of antigen-specific regulatory T cells (Tregs) is critical to uncover the mechanisms involved in the induction of indefinite allograft survival. RECENT FINDINGS: Myeloid dendritic cell-T-cell interactions are seminal events that determine the outcome of the immune response, and multiple in-vitro protocols suggest the generation of tolerogenic myeloid dendritic cells that modulate T-cell responses, and determine the outcome of the immune response to an allograft following adoptive transfer. We believe that identifying specific conditions that lead to the generation of tolerogenic myeloid dendritic cells and Tregs are critical for the manipulation of the immune response towards the development of transplantation tolerance. SUMMARY: We summarize recent findings regarding specific culture conditions that generate tolerogenic myeloid dendritic cells that induce T-cell hyporesponsiveness and Treg development, which represents a novel immunotherapeutic approach to promote the induction of indefinite graft survival prolongation. The interpretations presented here illustrate that different mechanisms govern the generation of tolerogenic myeloid dendritic cells, and we discuss the concomitant therapeutic implications.


Assuntos
Células Dendríticas/transplante , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Imunoterapia/métodos , Células Mieloides/transplante , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante , Animais , Técnicas de Cultura de Células , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Rejeição de Enxerto/imunologia , Humanos , Células Mieloides/imunologia
6.
Transplantation ; 102(12): e483-e493, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30211827

RESUMO

BACKGROUND: Airway epithelium is the primary target of trachea and lung transplant rejection, the degree of epithelial injury is closely correlated with obliterative bronchiolitis development. In this study, we investigated the cellular and molecular mechanisms of IL-17A-mediated airway epithelial injury after transplantation. METHODS: Murine orthotopic allogeneic trachea or lung transplants were implemented in wild type or RORγt mice. Recipients received anti-IL-17A or anti-IFNγ for cytokine neutralization, anti-CD8 for CD8 T-cell depletion, or STAT3 inhibitor to suppress type 17 CD4+/CD8+ T cell development. Airway injury and graft inflammatory cell infiltration were examined by histopathology and immunohistochemistry. Gene expression of IL-17A, IFNγ, perforin, granzyme B, and chemokines in grafts was quantitated by real-time RT-PCR. RESULTS: IL-17A and IFNγ were rapidly expressed and associated with epithelial injury and CD8 T-cell accumulation after allotransplantation. Depletion of CD8 T cells prevented airway epithelial injury. Neutralization of IL-17A or devoid of IL-17A production by RORγt deficiency improved airway epithelial integrity of the trachea allografts. Anti-IL-17A reduced the expression of CXCL9, CXCL10, CXCL11, and CCL20, and abolished CD8 T-cell accumulation in the trachea allografts. Inhibition of STAT3 activation significantly reduced IL-17A expression in both trachea and lung allografts; however, it increased IFNγ expression and cytotoxic activities, which resulted in the failure of airway protection. CONCLUSIONS: Our data reveal the critical role of IL-17A in mediating CD8 T effector response that causes airway epithelial injury and lung allograft rejection, and indicate that inhibition of STAT3 signals could drive CD8 T cells from Tc17 toward Tc1 development.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Epiteliais/metabolismo , Interleucina-17/metabolismo , Lesão Pulmonar/metabolismo , Transplante de Pulmão/efeitos adversos , Pulmão/metabolismo , Traqueia/metabolismo , Traqueia/transplante , Animais , Anticorpos Neutralizantes/administração & dosagem , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Interferon gama/metabolismo , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/deficiência , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Tempo , Traqueia/imunologia , Traqueia/patologia
7.
Curr Opin Immunol ; 16(5): 571-7, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15342001

RESUMO

T cell migration and trafficking are regulated by the well defined cellular processes of rolling, activation, tight adhesion, arrest and diapedesis. These processes are, in turn, controlled by molecular events involving integrins, selectins, chemokines and chemokine receptors. Recent studies have shown that sphingosine 1-phosphate receptors and their ligands are also important molecular modulators of migration and trafficking. Many of these molecules are appropriate targets for preventing allograft rejection or for achieving tolerance. Studies of migration and trafficking have also shown that the anatomic choreography of alloantigen presentation and T cell encounter with alloantigen and immunosuppression, are over-riding determinants of T cell priming versus tolerization.


Assuntos
Quimiotaxia de Leucócito/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Imunologia de Transplantes , Animais , Células Apresentadoras de Antígenos/imunologia , Moléculas de Adesão Celular/imunologia , Quimiocinas/imunologia , Humanos , Ativação Linfocitária/imunologia , Receptores de Lisoesfingolipídeo/imunologia , Transplante Homólogo
8.
Mucosal Immunol ; 8(2): 390-402, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25160819

RESUMO

Interleukin-23 (IL-23) responsive group 3 innate lymphoid cells (ILC3s) have been implicated in immune homeostasis and pathogenesis in the adult, but little is known about their roles in the newborn. Here we show that IL-23 promotes conversion of embryonic intestinal Lin(-)IL-23R(+)Thy1(+) cells into IL-22-producing Thy1(+)Sca-1(hi) ILC3s in vitro. Gut-specific expression of IL-23 also activated and expanded Thy1(+)Sca-1(hi) ILC3s, which produced IL-22, IL-17, interferon gamma (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) and were distinct from canonical CD4(+) lymphoid tissue inducer (LTi) cells. These ILC3s accumulated under the epithelium in intercellular adhesion molecule (ICAM)-1-positive cell aggregates together with neutrophils that disrupted the epithelium, leading to the formation of discrete intestinal erosions, bleeding, and neonatal death. Genetic and antibody depletion of ILC3s rescued the mice from neonatal death. Antibiotic treatment of pregnant mothers and offspring prolonged survival of IL-23 transgenic mice, suggesting a role for the commensal flora on ILC3-induced pathogenesis. Our results reveal a novel role for the IL-23-ILC3s axis in the pathogenesis of neonatal intestinal inflammation.


Assuntos
Imunidade Inata , Interleucina-23/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Animais , Antígenos de Superfície/metabolismo , Citocinas/metabolismo , Expressão Gênica , Humanos , Imunidade Inata/genética , Imunofenotipagem , Interleucina-23/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Intestinos/microbiologia , Intestinos/patologia , Camundongos , Camundongos Transgênicos , Infiltração de Neutrófilos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Permeabilidade , Fenótipo
9.
Immunol Res ; 54(1-3): 275-85, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22535241

RESUMO

Myeloid-derived suppressor cells (MDSC) are myeloid cells that suppress the immune response, a definition that reflects both their origin and their function. As negative regulators of the immune response, MDSC represent a novel therapeutic approach for manipulating the immune system toward tolerance or immunity. MDSC are present in cancer patients and tumor-bearing mice and are in part responsible for the inhibition of the cell-mediated immune response against the tumor. Our laboratories investigate the immunologic mechanisms of tumor acceptance mediated by MDSC, which can be exploited to prevent allograft rejection in transplantation. A better understanding of MDSC biology will open new avenues for therapeutic intervention, either by inhibiting their function (i.e. in cancer patients), or by enhancing their suppressive effects and promoting their expansion (i.e. in organ transplantation and alloimmune responses). In this review, we summarize some of the critical aspects of the immunoregulatory function of MDSC in cancer and transplantation and discuss their potential clinical applications.


Assuntos
Células Mieloides/imunologia , Neoplasias/imunologia , Transplante de Órgãos , Animais , Humanos , Células Mieloides/citologia , Linfócitos T/imunologia
10.
Cell Rep ; 2(3): 628-39, 2012 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-22959433

RESUMO

Peripheral tolerance to tumor antigens (Ags) is a major hurdle for antitumor immunity. Draining lymph nodes are considered the privileged sites for Ag presentation to T cells and for the onset of peripheral tolerance. Here, we show that the spleen is fundamentally important for tumor-induced tolerance. Splenectomy restores lymphocyte function and induces tumor regression when coupled with immunotherapy. Splenic CD11b(+)Gr-1(int)Ly6C(hi) cells, mostly comprising proliferating CCR2(+)-inflammatory monocytes with features of myeloid progenitors, expand in the marginal zone of the spleen. Here, they alter the normal tissue cytoarchitecture and closely associate with memory CD8(+) T cells, cross-presenting tumor Ags and causing their tolerization. Because of its high proliferative potential, this myeloid cell subset is also susceptible to low-dose chemotherapy, which can be exploited as an adjuvant to passive immunotherapy. CCL2 serum levels in cancer patients are directly related to the accumulation of immature myeloid cells and are predictive for overall survival in patients who develop a multipeptide response to cancer vaccines.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica , Monócitos/imunologia , Neoplasias/imunologia , Baço/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Humanos , Memória Imunológica , Camundongos , Monócitos/patologia , Neoplasias/patologia , Baço/patologia
11.
Methods Mol Biol ; 677: 127-47, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20941607

RESUMO

Dendritic cells (DC) are professional antigen-presenting cells (APCs) that modulate the outcome of the immune response toward immunity or tolerance. There are a large variety of DC subsets according to surface phenotype, function, and tissue distribution. Murine plasmacytoid DC (pDC) represent a distinctive DC population and are characterized by the expression of CD11c, B220, Gr-1, CD45RA, Ly49Q, BST2, and siglec-H on the cell surface. PDC act as immunogenic cell sentinels by secreting large amounts of type I interferon (IFN) in the lymph nodes in response to viral stimulation. PDC also act as tolerogenic cells when expressing the inducible tolerogenic enzyme indoleamine 2,3-dioxygenase (IDO), the inducible costimulator ligand (ICOS-L), and/or the programmed death 1 ligand (PD-L1), which mediate regulatory T-cell (Treg) development and suppression of self- and alloreactive cells. The PDC ability to induce Treg development is associated with capture and presentation of antigenic peptides associated with major histocompatibility complex (MHC) class I and II. Here, we provide the tools to study PDC development from bone marrow cultures, their antigen presentation properties, and their interactions with Treg under a tolerogenic setting of sterile inflammation.


Assuntos
Medula Óssea/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Diferenciação Celular/fisiologia , Células Cultivadas , Citometria de Fluxo , Homeostase/imunologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/citologia
12.
J Exp Med ; 208(5): 1069-82, 2011 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-21536742

RESUMO

Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/patologia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Linfócitos T/patologia , Transplante Homólogo
13.
Hum Immunol ; 71(11): 1061-6, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20705113

RESUMO

Myeloid derived suppressor cells (MDSC) contribute to the negative regulation of immune response in cancer patients. This review summarizes results on important issues related to MDSC biology, including expansion and activation of MDSC, phenotype, and subsets as well pathways and different mechanisms by which these cells exert their suppressive effect. Recent observations suggesting that MDSC may have roles in transplant tolerance are presented. Although therapeutic targeting and destruction of MDCS is of primary interest in cancer patients, in transplantation it will instead be necessary to induce, expand, and activate these cells; thus current possibilities for in vitro generation of MDSC are also discussed.


Assuntos
Rejeição de Enxerto/imunologia , Imunoterapia , Células Mieloides/metabolismo , Neoplasias/imunologia , Tolerância ao Transplante , Animais , Rejeição de Enxerto/terapia , Humanos , Tolerância Imunológica , Imunidade Celular , Células Mieloides/patologia , Neoplasias/patologia , Neoplasias/terapia , Transplante de Órgãos , Tolerância ao Transplante/imunologia , Evasão Tumoral
14.
J Clin Invest ; 120(7): 2486-96, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20551515

RESUMO

One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c+, CD11b+, or CD115+ cells, we identified a tolerogenic role for CD11b+CD115+Gr1+ monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1+ monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b+CD115+Gr1+ monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance.


Assuntos
Tolerância ao Transplante/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Ligante de CD40/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Sobrevivência de Enxerto/fisiologia , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Interleucina-2/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Tolerância ao Transplante/imunologia
15.
Blood ; 110(7): 2494-500, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17575072

RESUMO

T-bet plays a critical role in controlling IFNgamma expression, Th1 polarization, and CD8 cytolytic development. Its regulation has been demonstrated to be mostly IFNgamma/Stat1 dependent while IL-12/Stat4 independent. Here we show that IL-12/Stat4 binds to a distant highly conserved STAT-responsive T-bet enhancer, and induces IFNgamma/Stat1-independent T-bet expression in CD8 T cells. Luciferase reporter assay showed that both Stat4 and Stat1 activate reporter gene expression from constructs containing a wild-type but not mutated T-bet enhancer. Studies in virus-infected mice demonstrated that the IL-12/Stat4/T-bet cascade operates in vivo and regulates IFNgamma in CD8 T cells. Together, we provide a novel mechanism for T-bet regulation, and suggest that IL-12/Stat4/T-bet play an important role in CD8 effector responses.


Assuntos
Interferon gama/farmacologia , Interleucina-12/metabolismo , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT4/metabolismo , Transdução de Sinais , Proteínas com Domínio T/metabolismo , Adenoviridae/genética , Animais , Sequência de Bases , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Genes Reporter , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Ligação Proteica , Fator de Transcrição STAT4/deficiência , Fator de Transcrição STAT4/genética , Alinhamento de Sequência , Transdução de Sinais/efeitos dos fármacos , Proteínas com Domínio T/genética , Ativação Transcricional/genética
16.
Clin Transplant ; 20(6): 788-95, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17100731

RESUMO

In this review, we summarize how FTY720 came from the lab bench to the bedside by examining its structural similarities to natural occurring sphingosine analogues, the mechanism of action, and clinical applicability to not only transplantation but also autoimmune, oncological, and neurobiological fields. FTY720, a sphingosine 1-phosphate (S1P) analogue, promotes the survival of human and animal allografts by sequestering T lymphocytes within peripheral lymphoid tissue. The mechanism of sequestration is three-fold: (1) T lymphocytes are driven into peripheral lymph nodes in a chemokine dependent manner by FTY720; (2) FTY720 downregulates sphingosine 1-phosphate receptors (S1PRs) on the T lymphocyte surface, rendering it unable to migrate along a S1P gradient; and (3) FTY720 closes stromal gates on the abluminal side of the lymphatic endothelium. Future areas of investigation include developing S1P analogues that have specific agonist binding to S1PRs avoiding side effects seen in non-specific binding.


Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Órgãos , Receptores de Lisoesfingolipídeo/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Cloridrato de Fingolimode , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Humanos , Prognóstico , Propilenoglicóis/uso terapêutico , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/análogos & derivados , Esfingosina/uso terapêutico , Linfócitos T/metabolismo
17.
Nat Immunol ; 7(6): 652-62, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16633346

RESUMO

The induction of alloantigen-specific unresponsiveness remains an elusive goal in organ transplantation. Here we identify plasmacytoid dendritic cells (pDCs) as phagocytic antigen-presenting cells essential for tolerance to vascularized cardiac allografts. Tolerizing pDCs acquired alloantigen in the allograft and then moved through the blood to home to peripheral lymph nodes. In the lymph node, alloantigen-presenting pDCs induced the generation of CCR4+ CD4+ CD25+ Foxp3+ regulatory T cells (Treg cells). Depletion of pDCs or prevention of pDC lymph node homing inhibited peripheral Treg cell development and tolerance induction, whereas adoptive transfer of tolerized pDCs induced Treg cell development and prolonged graft survival. Thus, alloantigen-presenting pDCs home to the lymph nodes in tolerogenic conditions, where they mediate alloantigen-specific Treg cell development and allograft tolerance.


Assuntos
Células Dendríticas/imunologia , Transplante de Coração/imunologia , Isoantígenos/imunologia , Tolerância ao Transplante/imunologia , Transferência Adotiva , Animais , Apresentação de Antígeno/imunologia , Aorta/imunologia , Aorta/transplante , Sobrevivência de Enxerto/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos , Fagocitose/imunologia , Artéria Pulmonar/imunologia , Artéria Pulmonar/transplante , Linfócitos T Reguladores/imunologia
18.
J Immunol ; 175(5): 2913-24, 2005 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16116177

RESUMO

Chemokines and chemokine receptors are required for T cell trafficking and migration. Recent evidence shows that sphingosine 1-phosphate (S1P) and S1PRs are also important for some aspects of T cell migration, but how these two important receptor-ligand systems are integrated and coregulated is not known. In this study, we have investigated CCL19-CCR7 and CXCL12-CXCR4-driven migration of both splenic and peripheral lymph node (PLN) nonactivated and naive T cells, and used both S1P and the S1PR ligand, FTY720, to probe these interactions. The results demonstrate that splenic T cell migration to CCL19 or CXCL12 is enhanced by, but does not require, S1PR stimulation. In contrast, PLN T cell migration to CXCL12, but not CCL19, requires both chemokine and S1PR stimulation, and the requirement for dual receptor stimulation is particularly important for steps involving transendothelial migration. The results also demonstrate that: 1) splenic and PLN nonactivated and naive T cells use different molecular migration mechanisms; 2) CCR7 and CXCR4 stimulation engage different migration mechanisms; and 3) S1P and FTY720 have distinct S1PR agonist and antagonist properties. The results have important implications for understanding naive T cell entry into and egress from peripheral lymphoid organs, and we present a model for how S1P and chemokine receptor signaling may be integrated within a T cell.


Assuntos
Quimiocinas/fisiologia , Células Endoteliais/citologia , Linfonodos/citologia , Receptores de Lisoesfingolipídeo/fisiologia , Baço/citologia , Linfócitos T/fisiologia , Animais , Comunicação Celular , Movimento Celular , Quimiocina CCL19 , Quimiocina CXCL12 , Quimiocinas CC/fisiologia , Quimiocinas CXC/fisiologia , Cloridrato de Fingolimode , Lisofosfolipídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Propilenoglicóis/farmacologia , Esfingosina/análogos & derivados , Esfingosina/farmacologia
19.
J Immunol ; 174(11): 6993-7005, 2005 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-15905542

RESUMO

We previously demonstrated that L-selectin (CD62L)-dependent T cell homing to lymph nodes (LN) is required for tolerance induction to alloantigen. To explore the mechanisms of this observation, we analyzed the development and distribution of regulatory T cells (Treg), which play an important protective role against allograft rejection in transplantation tolerance. Alloantigen-specific tolerance was induced using either anti-CD2 plus anti-CD3 mAbs, or anti-CD40L mAbs plus donor-specific transfusion, in fully mismatched (BALB/c donor, C57BL/6 recipient) vascularized cardiac allografts. An expansion of CD4(+)CD25(+)CD62L(high) T cells was observed specifically within the LN of tolerant animals, but not in other anatomic sites or under nontolerizing conditions. These cells exhibited a substantial up-regulation of Foxp3 expression as measured by real-time PCR and by fluorescent immunohistochemistry, and possessed alloantigen-specific suppressor activity. Neither LN nor other lymphoid cells expressed the regulatory phenotype if recipients were treated with anti-CD62L mAbs, which both prevented LN homing and caused early allograft rejection. However, administration of FTY720, a sphingosine 1-phosphate receptor modulator that induces CD62L-independent T cell accumulation in the LNs, restored CD4(+)CD25(+) Treg in the LNs along with graft survival. These data suggest that alloantigen-specific Foxp3(+)CD4(+)CD25(+) Treg develop and are required within the LNs during tolerization, and provide compelling evidence that distinct lymphoid compartments play critical roles in transplantation tolerance.


Assuntos
Diferenciação Celular/imunologia , Proteínas de Ligação a DNA/biossíntese , Epitopos de Linfócito T/imunologia , Isoantígenos/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Movimento Celular/imunologia , Proliferação de Células , Células Cultivadas , Anergia Clonal/imunologia , Circulação Coronária/imunologia , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição Forkhead , Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Imunofenotipagem , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Receptores de Interleucina-2/biossíntese , Receptores de Retorno de Linfócitos/biossíntese , Linfócitos T Reguladores/citologia , Fatores de Transcrição , Tolerância ao Transplante/imunologia
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