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1.
J Immunol ; 202(11): 3226-3233, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31010850

RESUMO

Clonal deletion of T cells specific for self-antigens in the thymus has been widely studied, primarily by approaches that focus on a single receptor (using TCR transgenes) or a single specificity (using peptide-MHC tetramers). However, less is known about clonal deletion at the population level. In this article, we report an assay that measures cleaved caspase 3 to define clonal deletion at the population level. This assay distinguishes clonal deletion from apoptotic events caused by neglect and approximates the anatomic site of deletion using CCR7. This approach showed that 78% of clonal deletion events occur in the cortex in mice. Medullary deletion events were detected at both the semimature and mature stages, although mature events were associated with failed regulatory T cell induction. Using this assay, we showed that bone marrow-derived APC drive approximately half of deletion events at both stages. We also found that both cortical and medullary deletion rely heavily on CD28 costimulation. These findings demonstrate a useful strategy for studying clonal deletion within the polyclonal repertoire.


Assuntos
Células da Medula Óssea/imunologia , Caspase 3/metabolismo , Deleção Clonal , Receptores de Antígenos de Linfócitos T/metabolismo , Timo/imunologia , Animais , Apresentação do Antígeno , Apoptose , Autoantígenos/imunologia , Antígenos CD28/metabolismo , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteólise , Receptores CCR7 , Transdução de Sinais
2.
Immunity ; 50(2): 477-492.e8, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30737146

RESUMO

Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interferon gama/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Deleção Clonal/efeitos dos fármacos , Deleção Clonal/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
3.
Immunity ; 50(2): 280-282, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30784574

RESUMO

Combination immune checkpoint blockade targeting CTLA-4 and PD-1 is thought to reinvigorate exhausted T cells better than monotherapies. In this issue of Immunity, Pai et al. (2019) show that, in the setting of low tumor burden, this combination regimen promotes interferon-γ-dependent T cell hyperactivation and death and thus favors tumor progression.


Assuntos
Neoplasias , Linfócitos T , Antígeno CTLA-4 , Sobrevivência Celular , Deleção Clonal , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoterapia , Interferon gama
4.
Nat Immunol ; 19(12): 1379-1390, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420628

RESUMO

The T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR-pMHC-CD8 trimolecular 'catch bonds', whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR-pMHC and pMHC-CD8 bimolecular 'slip bonds'. Catch bonds were not intrinsic to either the TCR-pMHC or the pMHC-CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC-CD8 interaction to the intracellular interaction of CD8 with TCR-CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans-cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus.


Assuntos
Mecanotransdução Celular/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Deleção Clonal/imunologia , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/metabolismo , Timócitos/metabolismo
5.
Nat Commun ; 9(1): 4483, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367166

RESUMO

Targeting the expansion of pathogenic memory immune cells is a promising therapeutic strategy to prevent chronic autoimmune attacks. Here we investigate the therapeutic efficacy and mechanism of new anti-human IL-7Rα monoclonal antibodies (mAb) in non-human primates and show that, depending on the target epitope, a single injection of antagonistic anti-IL-7Rα mAbs induces a long-term control of skin inflammation despite repeated antigen challenges in presensitized monkeys. No modification in T cell numbers, phenotype, function or metabolism is observed in the peripheral blood or in response to polyclonal stimulation ex vivo. However, long-term in vivo hyporesponsiveness is associated with a significant decrease in the frequency of antigen-specific T cells producing IFN-γ upon antigen restimulation ex vivo. These findings indicate that chronic antigen-specific memory T cell responses can be controlled by anti-IL-7Rα mAbs, promoting and maintaining remission in T-cell mediated chronic inflammatory diseases.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Receptores de Interleucina-7/antagonistas & inibidores , Linfócitos T/imunologia , Animais , Doença Crônica , Deleção Clonal/imunologia , Modelos Animais de Doenças , Humanos , Memória Imunológica/imunologia , Inflamação/imunologia , Interferon gama/imunologia , Papio , Receptores de Interleucina-7/agonistas , Receptores de Interleucina-7/imunologia , Transdução de Sinais/efeitos dos fármacos , Pele/imunologia , Pele/patologia
6.
Front Immunol ; 9: 1950, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30237796

RESUMO

Delivery of gene therapy as well as of biologic therapeutics is often hampered by the immune response of the subject receiving the therapy. We have reported that effective gene therapy for hemophilia utilizing platelets as a delivery vehicle engenders profound tolerance to the therapeutic product. In this study, we investigated whether this strategy can be applied to induce immune tolerance to a non-coagulant protein and explored the fundamental mechanism of immune tolerance induced by platelet-targeted gene delivery. We used ovalbumin (OVA) as a surrogate non-coagulant protein and constructed a lentiviral vector in which OVA is driven by the platelet-specific αIIb promoter. Platelet-specific OVA expression was introduced by bone marrow transduction and transplantation. Greater than 95% of OVA was stored in platelet α-granules. Control mice immunized with OVA generated OVA-specific IgG antibodies; however, mice expressing OVA in platelets did not. Furthermore, OVA expression in platelets was sufficient to prevent the rejection of skin grafts from CAG-OVA mice, demonstrating that immune tolerance developed in platelet-specific OVA-transduced recipients. To assess the mechanism(s) involved in this tolerance we used OTII mice that express CD4+ effector T cells specific for an OVA-derived peptide. After platelet-specific OVA gene transfer, these mice showed normal thymic maturation of the T cells ruling against central tolerance. In the periphery, tolerance involved elimination of OVA-specific CD4+ effector T cells by apoptosis and expansion of an OVA-specific regulatory T cell population. These experiments reveal the existence of natural peripheral tolerance processes to platelet granule contents which can be co-opted to deliver therapeutically important products.


Assuntos
Plaquetas , Deleção Clonal/genética , Técnicas de Transferência de Genes , Terapia Genética/métodos , Tolerância Periférica/genética , Linfócitos T Reguladores/imunologia , Animais , Camundongos , Camundongos Transgênicos , Linfócitos T Reguladores/patologia
8.
J Immunol ; 201(7): 1907-1917, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30127089

RESUMO

In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T cells recognizing pancreatic ß cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed that the common H2-Kd and/or H2-Db class I molecules expressed by this strain aberrantly lose the ability to mediate the thymic deletion of pathogenic CD8+ T cell responses through interactions with T1D susceptibility genes outside the MHC. A gene(s) mapping to proximal chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T cells. Using an inducible model of thymic negative selection and mRNA transcript analyses, we initially identified an elevated Nfkbid expression variant as a likely NOD-proximal chromosome 7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T cells. CRISPR/Cas9-mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8+ T cells. These results indicated that allelic variants of Nfkbid contribute to the efficiency of intrathymic deletion of diabetogenic CD8+ T cells. However, although enhancing thymic deletion of pathogenic CD8+ T cells, ablating Nfkbid expression surprisingly accelerated T1D onset that was associated with numeric decreases in both regulatory T and B lymphocytes in NOD mice.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Cromossomos Humanos Par 7/genética , Diabetes Mellitus Tipo 1/imunologia , Proteínas I-kappa B/genética , Timo/imunologia , Alelos , Animais , Autoantígenos/imunologia , Diferenciação Celular , Células Cultivadas , Deleção Clonal , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Proteínas I-kappa B/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Polimorfismo Genético
9.
Exp Hematol ; 64: 45-58.e9, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29775646

RESUMO

Recent biochemical characterization of arsenic resistance protein 2 (Ars2) has established it as central in determining the fate of nascent ribonucleic acid (RNA) polymerase II (RNAPII) transcripts. Through interactions with the nuclear 5'-7-methylguanosine cap-binding complex, Ars2 promotes cotranscriptional processing coupled with nuclear export or degradation of several classes of RNAPII transcripts, allowing for gene expression programs that facilitate rapid and sustained proliferation of immortalized cells in culture. However, rapidly dividing cells in culture do not represent the physiological condition of the vast majority of cells in an adult mammal. To examine functions of Ars2 in a physiological setting, we generated inducible Ars2 knockout mice and found that deletion of Ars2 from adult mice resulted in defective hematopoiesis in bone marrow and thymus. Importantly, only some of this defect could be explained by the requirement of Ars2 for rapid proliferation, which we found to be cell-type specific in vivo. Rather, Ars2 was required for survival of developing thymocytes and for limiting differentiation of bone marrow resident long-term hematopoietic stem cells. As a result, Ars2 knockout led to rapid thymic involution and loss of the ability of mice to regenerate peripheral blood after myeloablation. These in vivo data demonstrate that Ars2 expression is important at several steps of hematopoiesis, likely because Ars2 acts on gene expression programs underlying essential cell fate decisions such as the decision to die,proliferate, or differentiate.


Assuntos
Hematopoese/fisiologia , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Animais , Apoptose , Divisão Celular Assimétrica , Medula Óssea/patologia , Medula Óssea/fisiologia , Autorrenovação Celular , Deleção Clonal , Ensaio de Unidades Formadoras de Colônias , Proteínas de Ligação a DNA , Regulação da Expressão Gênica , Hematopoese/genética , Células-Tronco Hematopoéticas/patologia , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Proteínas Nucleares/deficiência , Especificidade de Órgãos , Quimera por Radiação , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/metabolismo , Células Estromais/fisiologia , Timócitos/citologia , Timo/patologia , Fatores de Transcrição/deficiência
10.
Nat Commun ; 9(1): 1262, 2018 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-29593265

RESUMO

Medullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4+ thymocyte crosstalk regulates the thymus homing of SHPS-1+ conventional DCs (cDC), plasmacytoid DCs (pDC) and macrophages. This homing process is controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently, Ltα-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-κB subunits and increased thymic recruitment of cDCs, pDCs and macrophages. This enhanced migration depends mainly on the chemokine receptor CCR2, and increases thymic clonal deletion. Altogether, this study identifies a fine-tuning mechanism of T cell repertoire selection and paves the way for therapeutic interventions to treat autoimmune disorders.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Deleção Clonal , Linfotoxina-alfa/metabolismo , Timo/imunologia , Animais , Antígenos/imunologia , Células da Medula Óssea/imunologia , Quimiocinas/imunologia , Técnicas de Cocultura , Células Dendríticas/imunologia , Feminino , Deleção de Genes , Tolerância Imunológica , Ligantes , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal , NF-kappa B/metabolismo , Receptores CCR2/metabolismo , Linfócitos T/imunologia , Timócitos/imunologia
11.
Annu Rev Immunol ; 36: 843-864, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29490162

RESUMO

Recent progress in both conceptual and technological approaches to human immunology have rejuvenated a field that has long been in the shadow of the inbred mouse model. This is a healthy development both for the clinical relevance of immunology and for the fact that it is a way to gain access to the wealth of phenomenology in the many human diseases that involve the immune system. This is where we are likely to discover new immunological mechanisms and principals, especially those involving genetic heterogeneity or environmental influences that are difficult to model effectively in inbred mice. We also suggest that there are likely to be novel immunological mechanisms in long-lived, less fecund mammals such as human beings since they must remain healthy far longer than short-lived rodents in order for the species to survive.


Assuntos
Sistema Imunitário/fisiologia , Imunidade , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Evolução Biológica , Variação Biológica da População , Deleção Clonal/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica , Modelos Animais , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
12.
J Leukoc Biol ; 104(2): 275-284, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29485734

RESUMO

T-cells bearing the αßTCR play a vital role in defending the host against foreign pathogens and malignant transformation of self. Importantly, T-cells are required to remain tolerant to the host's own cells and tissues in order to prevent self-reactive responses that can lead to autoimmune disease. T-cells achieve the capacity for self/nonself discrimination by undergoing a highly selective and rigorous developmental program during their maturation in the thymus. This organ is unique in its ability to support a program of T-cell development that ensures the establishment of a functionally diverse αßTCR repertoire within the peripheral T-cell pool. The thymus achieves this by virtue of specialized stromal microenvironments that contain heterogeneous cell types, whose organization and function underpins their ability to educate, support, and screen different thymocyte subsets through various stages of development. These stages range from the entry of early T-cell progenitors into the thymus, through to the positive and negative selection of the αßTCR repertoire. The importance of the thymus medulla as a site for T-cell tolerance and the exit of newly generated T-cells into the periphery is well established. In this review, we summarize current knowledge on the developmental pathways that take place during αßT-cell development in the thymus. In addition, we focus on the mechanisms that regulate thymic egress and contribute to the seeding of peripheral tissues with newly selected self-tolerant αßT-cells.


Assuntos
Tolerância a Antígenos Próprios/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/citologia , Timo/imunologia , Animais , Diferenciação Celular/imunologia , Deleção Clonal/imunologia , Humanos
13.
Dev Comp Immunol ; 84: 48-61, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29408048

RESUMO

In teleosts, as in mammals, the immune system is tightly regulated by sexual steroid hormones, such as oestrogens. We investigated the effects of 17ß-oestradiol on the expression of several genes related to T cell development and resulting T cell subpopulations in sea bass, Dicentrarchus labrax, for a primary lymphoid organ, the thymus, and two secondary lymphoid organs, the head-kidney and the spleen. In parallel, the oxidative burst capacity was assessed in leucocytes of the secondary lymphoid organs. Apoptosis- and proliferation-related genes, indicative of B and T cell clonal selection and lymphoid progenitor activity, were not affected by elevated oestrogen-levels. Sex-related oestrogen-responsiveness in T cell and antigen-presenting cell markers was observed, the expression of which was differentially induced by oestrogen-exposure in the three lymphoid organs. Remarkably, in the spleen, oestrogen increased regulatory T cell-related gene expression was associated with a decrease in oxidative burst capacity. To the best of our knowledge, this study indicates for the first time that physiological levels of oestrogen are likely to promote immune tolerance by modulating thymic function (i.e., T cell development and output) and peripheral T cells in teleosts, similar to previously reported oestrogenic effects in mammals.


Assuntos
Células Apresentadoras de Antígenos/fisiologia , Linfócitos B/fisiologia , Bass/imunologia , Estrogênios/metabolismo , Subpopulações de Linfócitos T/fisiologia , Linfócitos T Reguladores/fisiologia , Animais , Bass/genética , Diferenciação Celular/genética , Deleção Clonal , Estrogênios/imunologia , Evolução Molecular , Feminino , Tolerância Imunológica/genética , Ativação Linfocitária , Masculino , Sexo
14.
Mucosal Immunol ; 11(3): 932-946, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29346349

RESUMO

Integrin α4ß7 mediates the trafficking of leukocytes, including CD4+ T cells, to lymphoid tissues in the gut. Virus mediated damage to the gut is implicated in HIV and SIV mediated chronic immune activation and leads to irreversible damage to the immune system. We employed an immuno-PET/CT imaging technique to evaluate the impact of an anti-integrin α4ß7 mAb alone or in combination with ART, on the distribution of both SIV infected cells and CD4+ cells in rhesus macaques infected with SIV. We determined that α4ß7 mAb reduced viral antigen in an array of tissues of the lung, spleen, axillary, and inguinal lymph nodes. These sites are not directly linked to α4ß7 mediated homing; however, the most pronounced reduction in viral load was observed in the colon. Despite this reduction, α4ß7 mAb treatment did not prevent an apparent depletion of CD4+ T cells in gut in the acute phase of infection that is characteristic of HIV/SIV infection. However, α4ß7 mAb appeared to facilitate the preservation or restoration of CD4+ T cells in gut tissues at later stages of infection. Since damage to the gut is believed to play a central role in HIV pathogenesis, these results support further evaluation of α4ß7 antagonists in the study and treatment of HIV disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Colo/virologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Animais , Anticorpos Monoclonais/metabolismo , Proteínas da Membrana Bacteriana Externa , Linfócitos T CD4-Positivos/virologia , Sobrevivência Celular , Deleção Clonal , Modelos Animais de Doenças , Humanos , Integrinas/imunologia , Macaca , Receptores de Superfície Celular , Carga Viral
15.
J Autoimmun ; 89: 139-148, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29366602

RESUMO

Regulatory T cells are critical for the generation and maintenance of peripheral tolerance. Conditional deletion of the transcriptional repressor NKAP in Tregs using Foxp3-YFP-cre NKAP conditional knockout mice causes aggressive autoimmunity characterized by thymic atrophy, lymphadenopathy, peripheral T cell activation, generation of autoantibodies, immune infiltration into several organs, and crusty skin at 3 weeks of age, similar to that of "scurfy" Foxp3-mutant mice. While Treg development in the thymus proceeds normally in the absence of NKAP, there is a severe loss of thymically-derived Tregs in the periphery. NKAP-deficient Tregs have a recent thymic emigrant phenotype, and are attacked by complement in a cell-intrinsic manner in the periphery. Previously, we demonstrated that NKAP is required for conventional T cell maturation as it prevents complement-mediated attack in the periphery. We now show that Tregs undergo a similar maturation process as conventional T cells, requiring NKAP to acquire complement resistance after thymic egress.


Assuntos
Proteínas Repressoras/metabolismo , Linfócitos T Reguladores/imunologia , Timo/patologia , Animais , Autoanticorpos/metabolismo , Autoimunidade/genética , Diferenciação Celular , Células Cultivadas , Deleção Clonal , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Camundongos Knockout , Proteínas Repressoras/genética
16.
Hum Immunol ; 79(5): 334-342, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29289741

RESUMO

This review focuses on mechanistic studies performed in recipients of non-myeloablative bone marrow transplant regimens developed at Massachusetts General Hospital in HLA-identical and HLA-mismatched haploidentical combinations, initially as a platform for treatment of hematologic malignancies with immunotherapy in the form of donor leukocyte infusions, and later in combination with donor kidney transplantation for the induction of allograft tolerance. In patients with permanent mixed chimerism, central deletion may be a major mechanism of long-term tolerance. In patients in whom donor chimerism is only transient, the kidney itself plays a significant role in maintaining long-term tolerance. A high throughput sequencing approach to identifying and tracking a significant portion of the alloreactive T cell receptor repertoire has demonstrated biological significance in transplant patients and has been useful in pointing to clonal deletion as a long-term tolerance mechanism in recipients of HLA-mismatched combined kidney and bone marrow transplants with only transient chimerism.


Assuntos
Transplante de Medula Óssea , Transplante de Rim , Monitorização Imunológica , Quimeras de Transplante/imunologia , Tolerância ao Transplante/imunologia , Animais , Deleção Clonal/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Linfócitos T Reguladores/imunologia , Transplantes/imunologia , Transplantes/patologia
17.
Curr Opin Immunol ; 49: 51-55, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29102863

RESUMO

Infections often precede the onset of autoimmune disease and molecular (or epitope) mimicry is a plausible link. Cross-reacting epitopes are common between an infecting microorganism and the host because negative selection of self-reactive T-cells and B-cells is frequently incomplete. Complete eradication could lead to major voids in the immunologic repertoire. The association of an autoimmune disease with a microbial epitope may signify a causal relationship with the organism, an indirect connection through bystander effects, persistent infection or coincidence. There are well-established examples of a microbial mimic inducing a defined model of autoimmune disease in experimental animals but such instances are still relatively rare in humans. Establishing epitope mimicry as a direct cause opens opportunities for preventing the disease. Current approaches to cancer immunotherapy provides new examples of epitope mimicry between cancer antigens and normal tissue antigens.


Assuntos
Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Imunoterapia/métodos , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Bactérias/imunologia , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/terapia , Deleção Clonal , Reações Cruzadas , Humanos , Epitopos Imunodominantes/imunologia , Mimetismo Molecular , Neoplasias/terapia
18.
J Immunol ; 199(12): 3959-3971, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29101311

RESUMO

Aire controls the fate of autoreactive thymocytes (i.e., clonal deletion or development into regulatory T cells [Tregs]) through transcriptional control of the expression of tissue-restricted self-antigens (TRAs) from medullary thymic epithelial cells (mTECs) and bone marrow (BM)-derived cells. Although TRAs expressed by mTECs and BM-derived cells are suggested to complement each other to generate a full spectrum of TRAs, little is known about the relative contribution of TRAs from each component for establishment of self-tolerance. Furthermore, the precise role of Aire in specific types of Aire-expressing APCs remains elusive. We have approached these issues by generating two different types of transgenic mouse (Tg) model, which express a prefixed model self-antigen driven by the insulin promoter or the Aire promoter. In the insulin-promoter Tg model, mTECs alone were insufficient for clonal deletion, and BM-derived APCs were required for this action by utilizing Ag transferred from mTECs. In contrast, mTECs alone were able to induce Tregs, although at a much lower efficiency in the absence of BM-derived APCs. Importantly, lack of Aire in mTECs, but not in BM-derived APCs, impaired both clonal deletion and production of Tregs. In the Aire-promoter Tg model, both mTECs and BM-derived APCs could independently induce clonal deletion without Aire, and production of Tregs was impaired by the lack of Aire in mTECs, but not in BM-derived APCs. These results suggest that the fate of autoreactive thymocytes together with the requirement for Aire depend on the cell types that express self-antigens and the types of APCs involved in tolerance induction.


Assuntos
Apresentação do Antígeno , Células Apresentadoras de Antígenos/imunologia , Autoantígenos/imunologia , Deleção Clonal/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Fatores de Transcrição/imunologia , Animais , Autoantígenos/biossíntese , Autoantígenos/genética , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica/imunologia , Técnicas de Introdução de Genes , Genes Sintéticos , Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ovalbumina/biossíntese , Ovalbumina/genética , Ovalbumina/imunologia , Regiões Promotoras Genéticas , Ratos , Organismos Livres de Patógenos Específicos , Timo/citologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transgenes
19.
J Immunol ; 199(8): 2713-2720, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28864471

RESUMO

Peripheral tolerance mechanisms exist to prevent autoimmune destruction by self-reactive T cells that escape thymic deletion. Dominant tolerance imposed by CD4+Foxp3+ T regulatory cells can actively control autoaggressive T cell responses. Tolerance mechanisms that act endogenous to the T cell also exist. These mechanisms include T cell inactivation (anergy) and deletion. A major difference between anergic T cells and T cells undergoing peripheral deletion is the capacity of the latter to still signal through MAPKs upon TCR stimulation, suggesting these signals may be required for T deletion. In this study, we used several different models of CD8 T cell deletion to investigate the contribution of MAPK activation. Using chemical inhibitors, we established that inhibition of p38, but not ERK or JNK, rescue T cells from undergoing peripheral deletion both in vitro and in vivo. Using T cell-specific murine lines genetically altered in expression of p38α, and mice in which p38α was deleted only in CD11c-expressing cells, we surprisingly found that CD8 T cell-intrinsic p38α activation was not responsible for increased survival, but rather that inhibition of p38α in the Ag-presenting dendritic cells prevented CD8 T cell deletion.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Deleção Clonal , Células Dendríticas/imunologia , Tolerância Periférica , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antígeno CD11c/metabolismo , Linhagem Celular , Apresentação Cruzada , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética
20.
Biosci Biotechnol Biochem ; 81(11): 2160-2163, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28934904

RESUMO

Superantigens (SAgs) are powerful T-cell stimulatory proteins. Because an atopic dermatitis (AD) model NC/Nga mice had two endogenous SAgs, namely minor lymphocyte-stimulating locus-1a (Mls-1a) and mouse mammary tumor virus (MMTV)(SHN), SAg-responsive T-cells bearing Vß5.1, Vß6, Vß8.1, Vß8.2, Vß8.3, Vß9, and Vß11 should be endogenously deleted. Here, we discuss that the endogenous SAgs-expression may be involved in AD-sensitivity in NC/Nga mice.


Assuntos
Deleção Clonal , Receptores de Antígenos de Linfócitos T/imunologia , Superantígenos/imunologia , Linfócitos T/imunologia , Animais , Vírus do Tumor Mamário do Camundongo/imunologia , Camundongos
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