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1.
Nat Immunol ; 15(3): 258-65, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24464130

RESUMO

The maintenance of immunological tolerance requires the deletion of self-reactive T cells in the thymus. The expression of genes encoding tissue-specific antigens (TSAs) by thymic epithelial cells is critical for this process and depends on activity of the transcriptional regulator Aire; however, the molecular mechanisms Aire uses to target loci encoding TSAs are unknown. Here we identified two Aire-interacting proteins known to be involved in gene repression, ATF7ip and MBD1, that were required for Aire's targeting of loci encoding TSAs. Moreover, Mbd1(-/-) mice developed pathological autoimmunity and had a defect in Aire-dependent thymic expression of genes encoding TSAs, which underscores the importance of Aire's interaction with the ATF7ip-MBD1 protein complex in maintaining central tolerance.


Assuntos
Tolerância Central/imunologia , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica , Proteínas Repressoras/imunologia , Fatores de Transcrição/imunologia , Animais , Autoantígenos/imunologia , Tolerância Central/genética , Proteínas de Ligação a DNA/genética , Citometria de Fluxo , Células HEK293 , Humanos , Immunoblotting , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Transfecção , Técnicas do Sistema de Duplo-Híbrido , Proteína AIRE
2.
Nature ; 559(7715): 627-631, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30022164

RESUMO

The thymus is responsible for generating a diverse yet self-tolerant pool of T cells1. Although the thymic medulla consists mostly of developing and mature AIRE+ epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought2. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers3. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.


Assuntos
Células Epiteliais/citologia , Células Epiteliais/metabolismo , Interleucina-4/metabolismo , Timócitos/citologia , Timo/citologia , Timo/metabolismo , Animais , Microambiente Celular , Quinases Semelhantes a Duplacortina , Feminino , Humanos , Tolerância Imunológica/imunologia , Interleucina-4/biossíntese , Interleucinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Timócitos/metabolismo , Timo/anatomia & histologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Proteína AIRE
3.
Immunity ; 39(3): 560-72, 2013 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-23993652

RESUMO

The autoimmune regulator (Aire) is essential for prevention of autoimmunity; its role is best understood in the thymus, where it promotes self-tolerance through tissue-specific antigen (TSA) expression. Recently, extrathymic Aire-expressing cells (eTACs) have been described in murine secondary lymphoid organs, but the identity of such cells and their role in immune tolerance remains unclear. Here we have shown that eTACs are a discrete major histocompatibility complex class II (MHC II)(hi), CD80(lo), CD86(lo), epithelial cell adhesion molecule (EpCAM)(hi), CD45(lo) bone marrow-derived peripheral antigen-presenting cell (APC) population. We also have demonstrated that eTACs can functionally inactivate CD4⁺ T cells through a mechanism that does not require regulatory T cells (Treg) and is resistant to innate inflammatory stimuli. Together, these findings further define eTACs as a distinct tolerogenic cell population in secondary lymphoid organs.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância a Antígenos Próprios , Fatores de Transcrição/metabolismo , Transferência Adotiva , Animais , Apresentação de Antígeno , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Neoplasias/metabolismo , Autoimunidade , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Células da Medula Óssea , Moléculas de Adesão Celular/metabolismo , Molécula de Adesão da Célula Epitelial , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Fatores de Transcrição/biossíntese , Proteína AIRE
4.
J Immunol ; 204(11): 2877-2886, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32269095

RESUMO

Central tolerance prevents autoimmunity, but also limits T cell responses to potentially immunodominant tumor epitopes with limited expression in healthy tissues. In peripheral APCs, γ-IFN-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of disulfide bond-containing proteins, including the self-antigen and melanoma Ag tyrosinase-related protein 1 (TRP1). The role of GILT in thymic Ag processing and generation of central tolerance has not been investigated. We found that GILT enhanced the negative selection of TRP1-specific thymocytes in mice. GILT expression was enriched in thymic APCs capable of mediating deletion, namely medullary thymic epithelial cells (mTECs) and dendritic cells, whereas TRP1 expression was restricted solely to mTECs. GILT facilitated MHC class II-restricted presentation of endogenous TRP1 by pooled thymic APCs. Using bone marrow chimeras, GILT expression in thymic epithelial cells (TECs), but not hematopoietic cells, was sufficient for complete deletion of TRP1-specific thymocytes. An increased frequency of TRP1-specific regulatory T (Treg) cells was present in chimeras with increased deletion of TRP1-specific thymocytes. Only chimeras that lacked GILT in both TECs and hematopoietic cells had a high conventional T/Treg cell ratio and were protected from melanoma challenge. Thus, GILT expression in thymic APCs, and mTECs in particular, preferentially facilitates MHC class II-restricted presentation, negative selection, and increased Treg cells, resulting in a diminished antitumor response to a tissue-restricted, melanoma-associated self-antigen.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Epiteliais/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias/imunologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Oxirredutases/metabolismo , Linfócitos T Reguladores/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Apresentação de Antígeno , Autoantígenos/metabolismo , Células Cultivadas , Tolerância Central , Seleção Clonal Mediada por Antígeno , Células Epiteliais/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética
5.
Am J Pathol ; 184(6): 1695-705, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24736166

RESUMO

Development of novel strategies to treat noninfectious posterior uveitis is an ongoing challenge, in part because of limited availability of animal models that mimic the naturally occurring disease in humans. Mice deficient in the autoimmune regulatory gene Aire develop a spontaneous T-cell and macrophage-mediated autoimmune uveitis that closely recapitulates human endogenous uveitis and thus provide a useful model for mechanistic and therapeutic investigations. Lymphocytic and mononuclear infiltration of the retina in Aire knockout (KO) mice triggers the onset of uveitis from initial retinal inflammation to eventual destruction of the neuroretina with loss of photoreceptors. The C-C chemokine receptor type 2 protein (CCR2) functions in directing monocyte and macrophage migration to inflamed tissues via interaction with monocyte chemotactic proteins. Using the Aire KO mouse model, we demonstrated an essential role for CCR2 in the pathogenesis of autoimmune-mediated uveitis. Loss of functional CCR2 effectively reduced immune cell infiltration and rescued the retina from destruction. CCR2-dependent migration of bone marrow-derived cells provided the driving force for retinal inflammation, with CCR2-expressing mononuclear cells contributing to retinal damage via recruitment of CD4(+) T cells. These studies identify the CCR2 pathway as a promising therapeutic target that may prove an effective approach to treat uveitis associated with autoimmunity.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Movimento Celular/imunologia , Receptores CCR2/imunologia , Retina/imunologia , Uveíte/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Linfócitos T CD4-Positivos/patologia , Movimento Celular/genética , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Monócitos/imunologia , Monócitos/patologia , Receptores CCR2/genética , Retina/patologia , Uveíte/genética , Uveíte/patologia
6.
Immunol Rev ; 241(1): 89-103, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21488892

RESUMO

The negative selection of self-reactive thymocytes depends on the expression of tissue-specific antigens by medullary thymic epithelial cells. The autoimmune regulator (Aire) protein plays an important role in turning on these antigens, and the absence of even one Aire-induced tissue-specific antigen in the thymus can lead to autoimmunity in the antigen-expressing target organ. Recently, Aire protein has been detected in peripheral lymphoid organs, suggesting that peripheral Aire plays a complementary role here. In these peripheral sites, Aire was found to regulate the expression of a group of tissue-specific antigens that is distinct from those expressed in the thymus. Furthermore, transgenic antigen expression in extrathymic Aire-expressing cells (eTACs) can mediate deletional tolerance, but the immunological relevance of Aire-dependent, endogenous tissue-specific antigens remains to be determined.


Assuntos
Autoantígenos/imunologia , Sistema Imunitário/imunologia , Tolerância Imunológica , Timo/imunologia , Fatores de Transcrição/imunologia , Animais , Autoimunidade , Deleção Clonal , Humanos , Sistema Imunitário/embriologia , Sistema Imunitário/crescimento & desenvolvimento , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Proteína AIRE
7.
J Med Chem ; 63(18): 10433-10459, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32865411

RESUMO

The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5'-(α,ß-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 (35) proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, 35 completely inhibited ADO production in both human cancer cells and CD8+ T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.


Assuntos
5'-Nucleotidase/antagonistas & inibidores , Adenosina/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fatores Imunológicos/farmacologia , Nucleosídeos/farmacologia , Organofosfonatos/farmacologia , Administração Oral , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Proteínas Ligadas por GPI/antagonistas & inibidores , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/síntese química , Fatores Imunológicos/farmacocinética , Macaca fascicularis , Camundongos Endogâmicos BALB C , Estrutura Molecular , Nucleosídeos/administração & dosagem , Nucleosídeos/síntese química , Nucleosídeos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/síntese química , Organofosfonatos/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
8.
Cancer Res ; 76(13): 3684-9, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27197182

RESUMO

ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. Antitumor immunity can be improved by ICOS-targeting therapies, but their mechanism of action remains unclear. Here, we define the role of ICOS signaling in antitumor immunity using a blocking, nondepleting antibody against ICOS ligand (ICOS-L). ICOS signaling provided critical support for the effector function of CD4(+) Foxp3(-) T cells during anti-OX40-driven tumor immune responses. By itself, ICOS-L blockade reduced accumulation of intratumoral T regulatory cells (Treg), but it was insufficient to substantially inhibit tumor growth. Furthermore, it did not impede antitumor responses mediated by anti-4-1BB-driven CD8(+) T cells. We found that anti-OX40 efficacy, which is based on Treg depletion and to a large degree on CD4(+) effector T cell (Teff) responses, was impaired with ICOS-L blockade. In contrast, the provision of additional ICOS signaling through direct ICOS-L expression by tumor cells enhanced tumor rejection and survival when administered along with anti-OX40 therapy. Taken together, our results showed that ICOS signaling during antitumor responses acts on both Teff and Treg cells, which have opposing roles in promoting immune activation. Thus, effective therapies targeting the ICOS pathway should seek to promote ICOS signaling specifically in effector CD4(+) T cells by combining ICOS agonism and Treg depletion. Cancer Res; 76(13); 3684-9. ©2016 AACR.


Assuntos
Adenocarcinoma/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Receptores OX40/metabolismo , Linfócitos T Reguladores/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/prevenção & controle , Animais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/prevenção & controle , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptores de Antígenos de Linfócitos T , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cell Stem Cell ; 13(2): 219-29, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23684540

RESUMO

Inducing immune tolerance to prevent rejection is a key step toward successful engraftment of stem-cell-derived tissue in a clinical setting. Using human pluripotent stem cells to generate thymic epithelial cells (TECs) capable of supporting T cell development represents a promising approach to reach this goal; however, progress toward generating functional TECs has been limited. Here, we describe a robust in vitro method to direct differentiation of human embryonic stem cells (hESCs) into thymic epithelial progenitors (TEPs) by precise regulation of TGFß, BMP4, RA, Wnt, Shh, and FGF signaling. The hESC-derived TEPs further mature into functional TECs that support T cell development upon transplantation into thymus-deficient mice. Importantly, the engrafted TEPs produce T cells capable of in vitro proliferation as well as in vivo immune responses. Thus, hESC-derived TEP grafts may have broad applications for enhancing engraftment in cell-based therapies as well as restoring age- and stress-related thymic decline.


Assuntos
Células-Tronco Embrionárias/citologia , Epitélio/crescimento & desenvolvimento , Linfócitos T/citologia , Timo/crescimento & desenvolvimento , Animais , Diferenciação Celular/imunologia , Células Epiteliais/citologia , Células Epiteliais/imunologia , Epitélio/metabolismo , Epitélio/transplante , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Modelos Biológicos , Transplante de Células-Tronco , Linfócitos T/imunologia , Timo/citologia , Timo/imunologia
10.
Cell Rep ; 5(1): 166-79, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24095736

RESUMO

Thymic epithelial cells in the medulla (mTECs) play a critical role in enforcing central tolerance through expression and presentation of tissue-specific antigens (TSAs) and deletion of autoreactive thymocytes. TSA expression requires autoimmune regulator (Aire), a transcriptional activator present in a subset of mTECs characterized by high CD80 and major histocompatibility complex II expression and a lack of potential for differentiation or proliferation. Here, using an Aire-DTR transgenic line, we show that short-term ablation specifically targets Aire(+) mTECs, which quickly undergo RANK-dependent recovery. Repeated ablation also affects Aire(-) mTECs, and using an inducible Aire-Cre fate-mapping system, we find that this results from the loss of a subset of mTECs that showed prior expression of Aire, maintains intermediate TSA expression, and preferentially migrates toward the center of the medulla. These results clearly identify a distinct stage of mTEC development and underscore the diversity of mTECs that play a key role in maintaining tolerance.


Assuntos
Células Epiteliais/citologia , Células Epiteliais/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/citologia , Timo/metabolismo , Animais , Diferenciação Celular/fisiologia , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Transdução de Sinais
11.
Sci Transl Med ; 5(206): 206ra139, 2013 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-24107778

RESUMO

Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes. Despite the connection between ILD and autoimmunity, it remains unclear whether ILD can develop from an autoimmune response that specifically targets the lung parenchyma. We examined a severe form of autoimmune disease, autoimmune polyglandular syndrome type 1 (APS1), and established a strong link between an autoimmune response to the lung-specific protein BPIFB1 (bactericidal/permeability-increasing fold-containing B1) and clinical ILD. Screening of a large cohort of APS1 patients revealed autoantibodies to BPIFB1 in 9.6% of APS1 subjects overall and in 100% of APS1 subjects with ILD. Further investigation of ILD outside the APS1 disorder revealed BPIFB1 autoantibodies present in 14.6% of patients with connective tissue disease-associated ILD and in 12.0% of patients with idiopathic ILD. The animal model for APS1, Aire⁻/⁻ mice, harbors autoantibodies to a similar lung antigen (BPIFB9); these autoantibodies are a marker for ILD. We found that a defect in thymic tolerance was responsible for the production of BPIFB9 autoantibodies and the development of ILD. We also found that immunoreactivity targeting BPIFB1 independent of a defect in Aire also led to ILD, consistent with our discovery of BPIFB1 autoantibodies in non-APS1 patients. Overall, our results demonstrate that autoimmunity targeting the lung-specific antigen BPIFB1 may contribute to the pathogenesis of ILD in patients with APS1 and in subsets of patients with non-APS1 ILD, demonstrating the role of lung-specific autoimmunity in the genesis of ILD.


Assuntos
Autoantígenos/imunologia , Proteínas de Transporte/metabolismo , Glicoproteínas/metabolismo , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/imunologia , Pulmão/patologia , Proteínas/metabolismo , Transferência Adotiva , Animais , Autoanticorpos/imunologia , Autoantígenos/metabolismo , Autoimunidade/imunologia , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Proteínas de Ligação a Ácido Graxo , Genótipo , Humanos , Tolerância Imunológica/imunologia , Camundongos , Especificidade de Órgãos , Poliendocrinopatias Autoimunes/imunologia , Ensaio Radioligante , Reprodutibilidade dos Testes , Timo/imunologia , Timo/transplante , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína AIRE
12.
J Clin Invest ; 121(4): 1251-3, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21436581

RESUMO

Myocarditis, or inflammation of the heart, is a potentially devastating disease that can result from both viral infection and autoimmune attack of self antigens in the heart. In the current issue of the JCI, Lv and colleagues use a genetically susceptible mouse model to show that myocarditis is a T cell-mediated autoimmune disease that occurs due to insufficient thymic negative selection of α-myosin-reactive T cells.


Assuntos
Tolerância Imunológica , Miocardite/imunologia , Animais , Modelos Animais de Doenças , Antígenos HLA-DQ/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Miocardite/etiologia , Miocardite/prevenção & controle , Linfócitos T/imunologia , Miosinas Ventriculares/imunologia
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