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1.
Nat Commun ; 11(1): 4504, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908131

RESUMO

The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.


Assuntos
Microambiente Celular/imunologia , Sistemas de Liberação de Medicamentos/instrumentação , Fator de Crescimento Neural/administração & dosagem , Regeneração Nervosa/efeitos dos fármacos , Traumatismos da Medula Espinal/terapia , Tecidos Suporte , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Preparações de Ação Retardada/administração & dosagem , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Interleucina-4/administração & dosagem , Lipossomos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Fator de Crescimento Neural/farmacocinética , Regeneração Nervosa/imunologia , Ratos , Recuperação de Função Fisiológica/imunologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Traumatismos da Medula Espinal/imunologia
2.
Science ; 369(6506): 984-988, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820125

RESUMO

Germinal center (GC) responses potentiate the generation of follicular regulatory T (TFR) cells. However, the molecular cues driving TFR cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (TFH) cells and T-B cell border-enriched fibroblastic reticular cells, is developmentally required for TFR cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing TFH cells as a distinct T cell population that develops after SOSTDC1- TFH cells and loses the ability to help B cells for antibody production. Notably, Sostdc1 ablation in TFH cells results in substantially reduced TFR cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT-ß-catenin axis and facilitates TFR cell differentiation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos B/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Centro Germinativo/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Mutantes , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
3.
Nat Commun ; 11(1): 3734, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709894

RESUMO

Medullary thymic epithelial cells (mTEC) contribute to the development of T cell tolerance by expressing and presenting tissue-restricted antigens (TRA), so that developing T cells can assess the self-reactivity of their antigen receptors prior to leaving the thymus. mTEC are a heterogeneous population of cells that differentially express TRA. Whether mTEC subsets induce distinct autoreactive T cell fates remains unclear. Here, we establish bacterial artificial chromosome (BAC)-transgenic mouse lines with biased mTEClo or mTEChi expression of model antigens. The transgenic lines support negative selection of antigen-specific thymocytes depending on antigen dose. However, model antigen expression predominantly by mTEClo supports TCRαß+ CD8αα intraepithelial lymphocyte development; meanwhile, mTEChi-restricted expression preferentially induces Treg differentiation of antigen-specific cells in these models to impact control of infectious agents and tumor growth. In summary, our data suggest that mTEC subsets may have a function in directing distinct mechanisms of T cell tolerance.


Assuntos
Antígenos/imunologia , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Linfócitos T/imunologia , Timo/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos/metabolismo , Infecções Bacterianas , Medula Óssea , Linhagem Celular Tumoral , Feminino , Tolerância Imunológica , Linfonodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T/metabolismo , Timócitos/imunologia , Fatores de Transcrição/genética
4.
Nat Commun ; 11(1): 3366, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632165

RESUMO

CD4+ T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4+ T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bethigh, T-betlow, and T-bet- subsets, with innate, Th1-like effector activity exclusively associated with T-bethigh cells. We further show that the latter population depends on IL-12 produced by CD8α+ type 1 dendritic cells (DC1) for its differentiation. Finally, our data demonstrate that this tonic IL-12 production requires TLR-MyD88 signaling independent of foreign agonists, and is further enhanced by CD40-CD40L interactions between DC1 and CD4+ T lymphocytes. We propose that optimal differentiation of T-bethigh MP lymphocytes at homeostasis is driven by self-recognition signals at both the DC and Tcell levels.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Homeostase/imunologia , Memória Imunológica/imunologia , Proteínas com Domínio T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/genética , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Comunicação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-12/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo
5.
Proc Natl Acad Sci U S A ; 117(29): 17156-17165, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32611812

RESUMO

Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77tg) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Vα14-Jα18 TCR-α chain gene into the Nur77tg (Nur77tg;Vα14tg) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-γ-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.


Assuntos
Diferenciação Celular , Tolerância Imunológica , Células T Matadoras Naturais , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Receptores de Antígenos de Linfócitos T , Timócitos
6.
Mol Immunol ; 125: 32-42, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32629323

RESUMO

Compelling evidence has demonstrated that Th17 cells play an essential role in the pathogenesis of multiple sclerosis (MS). Long noncoding RNAs (lncRNAs) have been confirmed as vital regulators of immune cell differentiation and other functions. However, whether and how lncRNAs influence Th17 cell differentiation and functional behaviors remain largely unclear. Here, we identified that a lncRNA, namely Gm15575, is specifically enriched in Th17 cells and spleen tissues of EAE mice. Functionally, knockdown of Gm15575 in Th17 cells suppressed the secretion of IL17A. Mechanistically, Gm15575 served as a competing endogenous RNA (ceRNA) to block the function of miR-686, positively regulating the expression of CCL7, a pro-inflammatory chemokine with high expression in Th17 cells, and Th17 differentiation. Taken together, our study revealed that Gm15575-miR-686 axis promoted the progression of EAE by regulating Th17 differentiation and expression of CCL7 which elucidated the pathogenesis of autoimmune diseases at genetic level. Gm15575 can be involved in the course of Th17-related autoimmune diseases.


Assuntos
Quimiocina CCL7/biossíntese , Encefalomielite Autoimune Experimental/genética , Regulação da Expressão Gênica/imunologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Células Th17/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Quimiocina CCL7/genética , Quimiocina CCL7/imunologia , Encefalomielite Autoimune Experimental/imunologia , Camundongos , MicroRNAs/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , RNA Longo não Codificante/imunologia , Regulação para Cima
7.
Nat Commun ; 11(1): 2857, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504069

RESUMO

Virtual memory T (TVM) cells are antigen-naïve CD8+ T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) has been proposed as a defining metabolic characteristic of antigen-experienced memory T (TMEM) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of TVM cells and their altered functionality with age, here we investigate TVM cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of TVM, but not TMEM, cells and it increases with age in both subsets. The elevated SRC observed in aged mouse TVM cells and human CD8+ T cells from older individuals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of TVM, but not TMEM, cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8+ T cells.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/ultraestrutura , Diferenciação Celular/imunologia , Proliferação de Células , Modelos Animais de Doenças , Feminino , Humanos , Vírus da Influenza A/imunologia , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/ultraestrutura , Adulto Jovem
8.
Mol Immunol ; 124: 190-197, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32593782

RESUMO

Understanding development of the dendritic cell (DC) subtypes continues to evolve. The origin and relationship of conventional DC type 1 (cDC1), cDC type 2 (cDC2) and plasmacytoid DCs (pDCs) to each other, and in relation to classic myeloid and lymphoid cells, has had a long and controversial history and is still not fully resolved. This review summarises the technological developments and findings that have been achieved at a clonal level, and how that has enhanced our knowledge of the process. It summarises the single cell lineage tracing technologies that have emerged, their application in in vitro and in vivo studies, in both mouse and human settings, and places the findings in a wider context of understanding haematopoiesis at a single cell or clonal level. In particular, it addresses the fate heterogeneity observed in many phenotypically defined progenitor subsets and how these findings have led to a departure from the classic ball-and-stick models of haematopoiesis to the emerging continuous model. Prior contradictions in DC development may be reconciled if they are framed within this revised model, where commitment to a lineage or cell type does not occur in an all-or-nothing process in defined progenitors but rather can occur at many stages of haematopoiesis in a dynamic process.


Assuntos
Células Dendríticas/citologia , Hematopoese , Animais , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Humanos
9.
Nat Immunol ; 21(7): 777-789, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32572238

RESUMO

T follicular helper (TFH) cells are a distinct type of CD4+ T cells that are essential for most antibody and B lymphocyte responses. TFH cell regulation and dysregulation is involved in a range of diseases. Bcl-6 is the lineage-defining transcription factor of TFH cells and its activity is essential for TFH cell differentiation and function. However, how Bcl-6 controls TFH biology has largely remained unclear, at least in part due to the intrinsic challenges of connecting repressors to gene upregulation in complex cell types with multiple possible differentiation fates. Multiple competing models were tested here by a series of experimental approaches to determine that Bcl-6 exhibits negative autoregulation and controls pleiotropic attributes of TFH differentiation and function, including migration, costimulation, inhibitory receptors and cytokines, via multiple repressor-of-repressor gene circuits.


Assuntos
Regulação da Expressão Gênica/imunologia , Centro Germinativo/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Repressoras/genética , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular , Movimento Celular/genética , Movimento Celular/imunologia , Sequenciamento de Cromatina por Imunoprecipitação , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Redes Reguladoras de Genes , Centro Germinativo/citologia , Humanos , Masculino , Camundongos , Mutação , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , RNA-Seq , Proteínas Repressoras/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
11.
Proc Natl Acad Sci U S A ; 117(23): 12969-12979, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32434911

RESUMO

CD5 is characterized as an inhibitory coreceptor with an important regulatory role during T cell development. The molecular mechanism by which CD5 operates has been puzzling and its function in mature T cells suggests promoting rather than repressing effects on immune responses. Here, we combined quantitative mass spectrometry and genetic studies to analyze the components and the activity of the CD5 signaling machinery in primary T cells. We found that T cell receptor (TCR) engagement induces the selective phosphorylation of CD5 tyrosine 429, which serves as a docking site for proteins with adaptor functions (c-Cbl, CIN85, CRKL), connecting CD5 to positive (PI3K) and negative (UBASH3A, SHIP1) regulators of TCR signaling. c-CBL acts as a coordinator in this complex enabling CD5 to synchronize positive and negative feedbacks on TCR signaling through the other components. Disruption of CD5 signalosome in mutant mice reveals that it modulates TCR signal outputs to selectively repress the transactivation of Foxp3 and limit the inopportune induction of peripherally induced regulatory T cells during immune responses against foreign antigen. Our findings bring insights into the paradigm of coreceptor signaling, suggesting that, in addition to providing dualistic enhancing or dampening inputs, coreceptors can engage concomitant stimulatory and inhibitory signaling events, which act together to promote specific functional outcomes.


Assuntos
Antígenos/imunologia , Antígenos CD5/metabolismo , Diferenciação Celular/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Reguladores/fisiologia , Animais , Antígenos CD5/genética , Diferenciação Celular/genética , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/genética , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Transdução de Sinais/genética , Transdução de Sinais/imunologia
12.
Prostate ; 80(10): 764-776, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32356608

RESUMO

BACKGROUND: Aging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion. METHODS: C57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic CD4+ T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling. RESULTS: Aged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naïve CD4+ T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. CD4+ T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged CD4+ T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice. CONCLUSIONS: These results indicate that age-related CD4+ T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Neoplasias da Próstata/imunologia , Células Th17/imunologia , Envelhecimento/imunologia , Animais , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , NF-kappa B/imunologia , Invasividade Neoplásica , Células PC-3 , Neoplasias da Próstata/patologia , Células Th17/patologia
13.
PLoS One ; 15(5): e0232432, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365067

RESUMO

CR3 and CR4, the leukocyte specific ß2-integrins, involved in cellular adherence, migration and phagocytosis, are often assumed to have similar functions. Previously however, we proved that under physiological conditions CR4 is dominant in the adhesion to fibrinogen of human monocyte-derived macrophages (MDMs) and dendritic cells (MDDCs). Here, using inflammatory conditions, we provide further evidence that the expression and function of CR3 and CR4 are not identical in these cell types. We found that LPS treatment changes their expression differently on MDMs and MDDCs, suggesting a cell type specific regulation. Using mAb24, specific for the high affinity conformation of CD18, we proved that the activation and recycling of ß2-integrins is significantly enhanced upon LPS treatment. Adherence to fibrinogen was assessed by two fundamentally different approaches: a classical adhesion assay and a computer-controlled micropipette, capable of measuring adhesion strength. While both receptors participated in adhesion, we demonstrated that CR4 exerts a dominant role in the strong attachment of MDDCs. Studying the formation of podosomes we found that MDMs retain podosome formation after LPS activation, whereas MDDCs lose this ability, resulting in a significantly reduced adhesion force and an altered cellular distribution of CR3 and CR4. Our results suggest that inflammatory conditions reshape differentially the expression and role of CR3 and CR4 in macrophages and dendritic cells.


Assuntos
Células Dendríticas/imunologia , Inflamação/imunologia , Integrina alfaXbeta2/imunologia , Antígeno de Macrófago 1/imunologia , Macrófagos/imunologia , Podossomos/imunologia , Anticorpos Bloqueadores/imunologia , Antígenos CD18/imunologia , Adesão Celular/imunologia , Adesão Celular/fisiologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Movimento Celular/fisiologia , Células Dendríticas/patologia , Células Dendríticas/fisiologia , Fibrinogênio/imunologia , Humanos , Técnicas In Vitro , Inflamação/patologia , Lipopolissacarídeos/imunologia , Macrófagos/patologia , Macrófagos/fisiologia , Fagocitose/imunologia , Fagocitose/fisiologia , Podossomos/patologia
14.
Nat Commun ; 11(1): 2198, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366944

RESUMO

The thymus supports multiple αß T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTßR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTßR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTßR controls CD104+CCL21+ mTEClow that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues.


Assuntos
Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células T Matadoras Naturais/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Antígenos CD1d/genética , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Proliferação de Células/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/imunologia , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/imunologia , Receptor beta de Linfotoxina/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/citologia , Timo/metabolismo
15.
Mol Immunol ; 123: 64-73, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32422416

RESUMO

T cells can help confer protective immunity by eliminating infections and tumors or drive immunopathology by damaging host cells. Both outcomes require a series of steps from the activation of naïve T cells to their clonal expansion, differentiation and migration to tissue sites. In addition to specific recognition of the antigen via the T cell receptor (TCR), multiple accessory signals from costimulatory molecules, cytokines and metabolites also influence each step along the progression of the T cell response. Current efforts to modify effector T cell function in many clinical contexts focus on the latter - which encompass antigen-independent and broad, contextual regulators. Not surprisingly, such approaches are often accompanied by adverse events, as they also affect T cells not relevant to the specific treatment. In contrast, fine tuning T cell responses by precisely targeting antigen-specific TCR signals has the potential to radically alter therapeutic strategies in a focused manner. Development of such approaches, however, requires a better understanding of functioning of the TCR and the biochemical signaling network coupled to it. In this article, we review some of the recent advances which highlight important roles of TCR signals throughout the activation and differentiation of T cells during an immune response. We discuss how, an appreciation of specific signaling modalities and variant ligands that influence the function of the TCR has the potential to influence design principles for the next generation of pharmacologic and cellular therapies, especially in the context of tumor immunotherapies involving adoptive cell transfers.


Assuntos
Transferência Adotiva/métodos , Imunidade Celular/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Diferenciação Celular/imunologia , Humanos , Imunoterapia/métodos , Ativação Linfocitária , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Transdução de Sinais/imunologia
16.
Prostate ; 80(11): 811-823, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32427375

RESUMO

BACKGROUND: Exosomes secreted by tumor cells can be regarded as carriers of tumor-associated antigens and have potential value in tumor immunotherapy. The aim of this study was to evaluate the antitumor efficacy of a novel exosomal vaccine (interferon-γ [IFN-γ]-modified exosomal vaccine) in prostate cancer. METHODS: Prostate cancer cell-derived exosomes were used to prepare the exosomal vaccine using our protein-anchoring technique. The immunogenicity and therapeutic efficacy of the exosomes was evaluated by measuring the effects of the exosomal vaccine on M1 macrophage differentiation, the ability of macrophages to engulf the exosomes, the production of antibodies against exosomes, and tumor angiogenesis and metastasis, and tumor growth. RESULTS: The IFN-γ fusion protein was efficiently anchored on the surface of prostate cancer cell-derived exosomes and retained its bioactivity. The IFN-γ-exosomal vaccine increased the number of M1 macrophages, enhanced the ability of M1 macrophages to engulf RM-1 cell-derived exosomes, and induced the production of specific antibodies against exosomes. The exosomal vaccine downregulated the expression of vascular endothelial growth factor receptor 2 and attenuated the effect of exosomes in promoting tumor metastasis. The proportions of CD4+ , CD8+ , and IFN-γ+ CD8+ T cells in the exosomal vaccine group were the highest among the four groups. Interestingly, the IFN-γ-exosomal vaccine decreased the percentage of Tregs and downregulated the expression of programed death-ligand 1 and indoleamine 2, 3-dioxygenase 1 in the tumor environment. The exosomal vaccine significantly inhibited tumor growth and prolonged the survival time of mice with prostate cancer. The exosomal and tumor cell vaccines had a good synergistic effect in promoting tumor immunity. CONCLUSIONS: The novel exosomal vaccine induced an immune response that cleared prostate cancer cell-derived exosomes, thereby eliminating the regulatory effect of the exosomes. This study may provide experimental evidence for the use of exosomes as a therapeutic tool or target in immunotherapy for human prostate cancer.


Assuntos
Vacinas Anticâncer/farmacologia , Exossomos/imunologia , Interferon gama/farmacologia , Neoplasias da Próstata/terapia , Animais , Anticorpos Antineoplásicos/biossíntese , Anticorpos Antineoplásicos/imunologia , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Vacinas Anticâncer/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Citocinas/sangue , Citocinas/imunologia , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interferon gama/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias da Próstata/imunologia , Distribuição Aleatória , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia
17.
Nat Immunol ; 21(7): 766-776, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32424367

RESUMO

Tissue-resident memory T (TRM) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of TRM cells are incompletely understood. Here we show that type 1 regulatory T (Treg) cells, which express the transcription factor T-bet, promote the generation of CD8+ TRM cells. The absence of T-bet-expressing type 1 Treg cells reduces the presence of TRM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 Treg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8+ T cells and Treg cell expression of integrin-ß8 endows the bioavailability of transforming growth factor-ß in the microenvironment, thereby promoting the generation of CD8+ TRM cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Memória Imunológica , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/transplante , Coccidiose/imunologia , Coccidiose/parasitologia , Modelos Animais de Doenças , Eimeria/imunologia , Feminino , Humanos , Cadeias beta de Integrinas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Receptores CXCR3/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante , Fator de Crescimento Transformador beta/metabolismo
18.
Cell Prolif ; 53(5): e12802, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32291850

RESUMO

OBJECTIVES: During human pregnancy, the endothelial cells of the uterine spiral arteries (SPA) are extensively replaced by a subtype of placental trophoblasts, endovascular extravillous trophoblasts (enEVTs), thus establishing a placental-maternal circulation. On this pathway, foetus-derived placental villi and enEVTs bath into the maternal blood that perfuses along SPA being not attacked by the maternal lymphocytes. We aimed to reveal the underlying mechanism of such immune tolerance. METHODS: In situ hybridization, immunofluorescence, ELISA and FCM assay were performed to examine TGF-ß1 expression and distribution of regulatory T cells (Tregs) along the placental-maternal circulation route. The primary enEVTs, interstitial extravillous trophoblasts (iEVTs) and decidual endothelial cells (dECs) were purified by FACS, and their conditioned media were collected to treat naïve CD4+ T cells. Treg differentiation was measured by FLOW and CFSE assays. RESULTS: We found that enEVTs but not iEVTs or dECs actively produced TGF-ß1. The primary enEVTs significantly promoted naïve CD4+ T-cell differentiation into immunosuppressive FOXP3+ Tregs, and this effect was dependent on TGF-ß1. In recurrent spontaneous abortion (RSA) patients, an evidently reduced proportion of TGF-ß1-producing enEVTs and their ability to educate Tregs differentiation were observed. CONCLUSIONS: Our findings demonstrate a unique immune-regulatory characteristic of placental enEVTs to develop immune tolerance along the placental-maternal circulation. New insights into the pathogenesis of RSA are also suggested.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Placenta/imunologia , Linfócitos T Reguladores/imunologia , Trofoblastos/imunologia , Adulto , Animais , Células Endoteliais/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Fator de Crescimento Transformador beta1/imunologia
19.
PLoS Pathog ; 16(4): e1008527, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32348365

RESUMO

The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS signaling in secondary immune responses is largely unexplored. Here we show that memory T cell formation and maintenance are influenced by persistent infection with P. chabaudi chabaudi AS infection, as memory T cell numbers decline in wild-type and Icos-/- mice after drug-clearance. Following drug-clearance Icos-/- mice display a relapsing parasitemia that occurs more frequently and with higher peaks compared to wild-type mice after re-challenge. The secondary immune response in Icos-/- mice is characterized by significant impairment in the expansion of effector cells with a Tfh-like phenotype, which is associated with a diminished and delayed parasite-specific Ab response and the absence of germinal centers. Similarly, the administration of an anti-ICOSL antagonizing antibody to wild-type mice before and after reinfection with P. c. chabaudi AS leads to an early defect in Tfh cell expansion and parasite-specific antibody production, confirming a need for ICOS-ICOSL interactions to promote memory B cell responses. Furthermore, adoptive transfer of central memory T (TCM) cells from wild-type and Icos-/- mice into tcrb-/- mice to directly evaluate the ability of TCM cells to give rise to Tfh cells revealed that TCM cells from wild-type mice acquire a mixed Th1- and Tfh-like phenotype after P. c. chabaudi AS infection. While TCM cells from Icos-/- mice expand and display markers of activation to a similar degree as their WT counterparts, they displayed a reduced capacity to upregulate markers indicative of a Tfh cell phenotype, resulting in a diminished humoral response. Together these findings verify that ICOS signaling in memory T cells plays an integral role in promoting T cell effector responses during secondary infection with P. c. chabaudi AS.


Assuntos
Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Centro Germinativo/imunologia , Imunidade Humoral/imunologia , Memória Imunológica , Ativação Linfocitária/imunologia , Malária/imunologia , Malária/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium chabaudi/metabolismo , Plasmodium chabaudi/patogenicidade , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/metabolismo
20.
Med Sci (Paris) ; 36(3): 253-260, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32228844

RESUMO

Upon priming by dendritic cells, naïve CD4 T lymphocytes are exposed to distinct molecular environments depending on the nature of the pathological stimulus. In response, they mobilize different gene networks that establish lineage-specific developmental programs, and coordinate the acquisition of specific phenotype and functions. Accordingly, CD4 T cells are capable of differentiation into a large variety of functionally-distinct T helper (Th) cell subsets. In this review, we describe the molecular events that control CD4 T cell differentiation at the level of the chromatin. We insist on recent works that have highlighted the key role of H3K9me3-dependent epigenetic mechanisms in the regulation of T cell identity. Interestingly, these pathways shape and control the developmental programs at least in part through the regulation of endogenous retroviruses-derived sequences that have been exapted into cis-regulatory modules of Th genes.


Assuntos
Retrovirus Endógenos/fisiologia , Fenômenos do Sistema Imunológico/fisiologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/imunologia , Epigênese Genética/fisiologia , Humanos , Ativação Linfocitária/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/fisiologia
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