RESUMO
The paracaspase Malt1 is a key regulator of canonical NF-κB activation downstream of multiple receptors in both immune and nonimmune cells. Genetic disruption of Malt1 protease function in mice and MALT1 mutations in humans results in reduced regulatory T cells and a progressive multiorgan inflammatory pathology. In this study, we evaluated the altered immune homeostasis and autoimmune disease in Malt1 protease-deficient (Malt1PD) mice and the Ags driving disease manifestations. Our data indicate that B cell activation and IgG1/IgE production is triggered by microbial and dietary Ags preferentially in lymphoid organs draining mucosal barriers, likely as a result of dysregulated mucosal immune homeostasis. Conversely, the disease was driven by a polyclonal T cell population directed against self-antigens. Characterization of the Malt1PD T cell compartment revealed expansion of T effector memory cells and concomitant loss of a CD4+ T cell population that phenotypically resembles anergic T cells. Therefore, we propose that the compromised regulatory T cell compartment in Malt1PD animals prevents the efficient maintenance of anergy and supports the progressive expansion of pathogenic, IFN-γ-producing T cells. Overall, our data revealed a crucial role of the Malt1 protease for the maintenance of intestinal and systemic immune homeostasis, which might provide insights into the mechanisms underlying IPEX-related diseases associated with mutations in MALT1.
Assuntos
Autoimunidade/imunologia , Homeostase/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Linfócitos T Reguladores/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/deficiência , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genéticaRESUMO
Plasmacytoid dendritic cells (pDCs) exhibit both innate and adaptive functions. In particular they are the main source of type I IFNs and directly impact T cell responses through antigen presentation. We have previously demonstrated that during experimental autoimmune encephalomyelitis (EAE) initiation, myelin-antigen presentation by pDCs is associated with suppressive Treg development and results in attenuated EAE. Here, we show that pDCs transferred during acute disease phase confer recovery from EAE. Clinical improvement is associated with migration of injected pDCs into inflamed CNS and is dependent on the subsequent and selective chemerin-mediated recruitment of endogenous pDCs to the CNS. The protective effect requires pDC pre-loading with myelin antigen, and is associated with the modulation of CNS-infiltrating pDC phenotype and inhibition of CNS encephalitogenic T cells. This study may pave the way for novel pDC-based cell therapies in autoimmune diseases, aiming at specifically modulating pathogenic cells that induce and sustain autoimmune inflammation.
Assuntos
Transferência Adotiva , Quimiotaxia/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Animais , Autoantígenos/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Quimiocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Knockout , Bainha de Mielina/imunologia , Receptores de Quimiocinas , Receptores Acoplados a Proteínas G/metabolismo , Medula Espinal/imunologia , Medula Espinal/metabolismo , Medula Espinal/patologiaRESUMO
Plasmacytoid dendritic cells (pDCs) have been shown to both mediate and prevent autoimmunity, and the regulation of their immunogenic versus tolerogenic functions remains incompletely understood. Here we demonstrate that, compared to other cells, pDCs are the major expressors of Indoleamine-2,3-dioxygenase (IDO) in steady-state lymph nodes (LNs). IDO expression by LN pDCs was closely dependent on MHCII-mediated, antigen-dependent, interactions with Treg. We further established that IDO production by pDCs was necessary to confer suppressive function to Tregs. During EAE development, IDO expression by pDCs was required for the generation of Tregs capable of dampening the priming of encephalitogenic T cell and disease severity. Thus, we describe a novel crosstalk between pDCs and Tregs: Tregs shape tolerogenic functions of pDCs prior to inflammation, such that pDCs in turn, promote Treg suppressive functions during autoimmunity.
Assuntos
Autoimunidade/imunologia , Células Dendríticas/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/genética , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/metabolismo , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Citometria de Fluxo , Regulação Enzimológica da Expressão Gênica , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Linfonodos/enzimologia , Linfonodos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/metabolismoRESUMO
To investigate the role of Toll-like receptor 9 (TLR9) in innate immunity to Mycobacterium avium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control of M. avium infection. However, TLR9 KO or TLR2 KO spleen cells displayed normal M. avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4(+) T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production by M. avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes in M. avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control of M. avium infection is not related to the induction of Th1 responses.
Assuntos
Células Th1/imunologia , Receptor Toll-Like 9/imunologia , Tuberculose/imunologia , Animais , Separação Celular , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe II/biossíntese , Antígenos de Histocompatibilidade Classe II/imunologia , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium avium/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Th1/metabolismo , Receptor 2 Toll-Like/imunologia , Receptor Toll-Like 9/metabolismo , Tuberculose/patologia , Tuberculose/veterináriaRESUMO
Lymphatic endothelial cells (LECs) chemoattract naïve T cells and promote their survival in the lymph nodes, and can cross-present antigens to naïve CD8+ T cells to drive their proliferation despite lacking key costimulatory molecules. However, the functional consequence of LEC priming of CD8+ T cells is unknown. Here, we show that while many proliferating LEC-educated T cells enter early apoptosis, the remainders comprise a long-lived memory subset, with transcriptional, metabolic, and phenotypic features of central memory and stem cell-like memory T cells. In vivo, these memory cells preferentially home to lymph nodes and display rapid proliferation and effector differentiation following memory recall, and can protect mice against a subsequent bacterial infection. These findings introduce a new immunomodulatory role for LECs in directly generating a memory-like subset of quiescent yet antigen-experienced CD8+ T cells that are long-lived and can rapidly differentiate into effector cells upon inflammatory antigenic challenge.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Endoteliais/fisiologia , Animais , Proliferação de Células , Células Endoteliais/imunologia , Perfilação da Expressão Gênica , Memória Imunológica , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Acute kidney injury (AKI) and chronic kidney diseases are associated with high mortality and morbidity. Although the underlying mechanisms determining the transition from acute to chronic injury are not completely understood, immune-mediated processes are critical in renal injury. We have performed a comparison of 2 mouse models leading to either kidney regeneration or fibrosis. Using global gene expression profiling we could identify immune-related pathways accounting for the majority of the observed transcriptional changes during fibrosis. Unbiased examination of the immune cell composition, using single-cell RNA sequencing, revealed major changes in tissue-resident macrophages and T cells. Following injury, there was a marked increase in tissue-resident IL-33R+ and IL-2Ra+ regulatory T cells (Tregs). Expansion of this population before injury protected the kidney from injury and fibrosis. Transcriptional profiling of Tregs showed a differential upregulation of regenerative and proangiogenic pathways during regeneration, whereas in the fibrotic environment they expressed markers of hyperactivation and fibrosis. Our data point to a hitherto underappreciated plasticity in Treg function within the same tissue, dictated by environmental cues. Overall, we provide a detailed cellular and molecular characterization of the immunological changes during kidney injury, regeneration, and fibrosis.
Assuntos
Injúria Renal Aguda/imunologia , Linfócitos T Reguladores/imunologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/genética , Injúria Renal Aguda/prevenção & controle , Animais , Biópsia , Modelos Animais de Doenças , Fibrose/genética , Fibrose/imunologia , Fibrose/prevenção & controle , Perfilação da Expressão Gênica , Interleucina-2/imunologia , Interleucina-33/imunologia , Rim/patologia , Rim/fisiopatologia , Camundongos , Regeneração , Traumatismo por Reperfusão/complicaçõesRESUMO
Sm14 and paramyosin are two major Schistosoma mansoni vaccine candidate antigens. Recently, we have identified Sm14 and paramyosin epitopes that are recognized by T cells of resistant individuals living in endemic areas for schistosomiasis. Herein, mice were immunized with these peptides separately or in association in order to evaluate their vaccine potential. Immunization of mice with Sm14 peptides alone or mixed with paramyosin peptides was able to induce 26%-36.7% or 28%-29.2% of worm burden reduction, 67% or 46% of intestinal eggs reduction and also 54%-61% or 43%-52% of liver pathology reduction, respectively. Protection was associated with a Th1 type of immune response induced by Sm14 peptide immunization. In contrast, paramyosin peptide vaccination did not engender protective immunity or liver pathology reduction and immunization was associated with a Th2 type of immune response.
Assuntos
Epitopos de Linfócito T/imunologia , Proteínas de Transporte de Ácido Graxo/imunologia , Proteínas de Helminto/imunologia , Fígado/imunologia , Esquistossomose mansoni/prevenção & controle , Células Th1/imunologia , Tropomiosina/imunologia , Animais , Anticorpos Anti-Helmínticos/sangue , Citocinas/biossíntese , Feminino , Intestinos/parasitologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Contagem de Ovos de Parasitas , Schistosoma mansoni/imunologia , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
How lymph node stromal cells (LNSCs) shape peripheral T-cell responses remains unclear. We have previously demonstrated that murine LNSCs, lymphatic endothelial cells (LECs), blood endothelial cells (BECs), and fibroblastic reticular cells (FRCs) use the IFN-γ-inducible promoter IV (pIV) of the MHC class II (MHCII) transactivator CIITA to express MHCII. Here, we show that aging mice (>1 yr old) in which MHCII is abrogated in LNSCs by the selective deletion of pIV exhibit a significant T-cell dysregulation in LNs, including defective Treg and increased effector CD4+ and CD8+ T-cell frequencies, resulting in enhanced peripheral organ T-cell infiltration and autoantibody production. The proliferation of LN-Tregs interacting with LECs increases following MHCII up-regulation by LECs upon aging or after exposure to IFN-γ, this effect being abolished in mice in which LECs lack MHCII. Overall, our work underpins the importance of LNSCs, particularly LECs, in supporting Tregs and T-cell tolerance.
RESUMO
Evidence has recently emerged that butyrophilins, which are members of the extended B7 family of co-stimulatory molecules, have diverse functions in the immune system. We found that the human and mouse genes encoding butyrophilin-2A2 (BTN2A2) are regulated by the class II trans-activator and regulatory factor X, two transcription factors dedicated to major histocompatibility complex class II expression, suggesting a role in T cell immunity. To address this, we generated Btn2a2-deficient mice. Btn2a2(-/-) mice exhibited enhanced effector CD4(+) and CD8(+) T cell responses, impaired CD4(+) regulatory T cell induction, potentiated antitumor responses, and exacerbated experimental autoimmune encephalomyelitis. Altered immune responses were attributed to Btn2a2 deficiency in antigen-presenting cells rather than T cells or nonhematopoietic cells. These results provide the first genetic evidence that BTN2A2 is a co-inhibitory molecule that modulates T cell-mediated immunity.
Assuntos
Genes MHC da Classe II , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Butirofilinas , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Regulação da Expressão Gênica , Humanos , Imunidade Celular , Glicoproteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição de Fator Regulador X , Transativadores/genética , Transativadores/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
Although autophagy is a process that has been studied for several years its link with antigen presentation and T cell immunity has only recently emerged. Autophagy, which means "self-eating," is important to maintain cell homeostasis and refers to a collection of mechanisms that delivers intracellular material for degradation into lysosomes. Among them, macroautophagy pathway has many implications in different biological processes, including innate and adaptive immunity. In particular, macroautophagy can provide a substantial source of intracellular antigens for loading onto MHC class II molecules using the alternative MHC class II pathway. Through autophagosomes, endogenous self-antigens as well as antigens derived from intracellular pathogens can be delivered to MHC class II compartment and presented to CD4(+) T cells. The pathway will, therefore, impact both peripheral T cell tolerance and the pathogen specific immune response. This review will describe the contribution of autophagy to intracellular presentation of endogenous self- or pathogen-derived antigens via MHC class II and its consequences on CD4(+) T cell responses.
RESUMO
Dendritic cells (DCs), and more recently lymph node stromal cells (LNSCs), have been described to tolerize self-reactive CD8(+) T cells in LNs. Although LNSCs express MHCII, it is unknown whether they can also impact CD4(+) T cell functions. We show that the promoter IV (pIV) of class II transactivator (CIITA), the master regulator of MHCII expression, controls endogenous MHCII expression by LNSCs. Unexpectedly, LNSCs also acquire peptide-MHCII complexes from DCs and induce CD4(+) T cell dysfunction by presenting transferred complexes to naive CD4(+) T cells and preventing their proliferation and survival. Our data reveals a novel, alternative mechanism where LN-resident stromal cells tolerize CD4(+) T cells through the presentation of self-antigens via transferred peptide-MHCII complexes of DC origin.
Assuntos
Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Tolerância Imunológica/imunologia , Linfonodos/imunologia , Células Estromais/imunologia , Animais , Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Células Cultivadas , Células Dendríticas/metabolismo , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon gama/imunologia , Interferon gama/farmacologia , Linfonodos/citologia , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Peptídeos/imunologia , Peptídeos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/metabolismo , Transativadores/genética , Transativadores/imunologia , Transativadores/metabolismoRESUMO
Objective: The study's goal has been to gain further knowledge about the experiences of family members of pregnant adolescents assisted by the Family Health Strategies in Montes Claros city, MG, about early pregnancy. Methods: It is a descriptive study with a qualitative approach, in which 10 relatives of pregnant adolescents were interviewed. Results: It was perceived by the research that the adolescents' relatives refer to sexuality as a sexual act only. Interviewees relate early gestation to various factors. The acceptance of pregnancy has been referred positively, even when it is unexpected. Conclusion: The behaviors adopted by the adolescents' relatives varies from advising up to providing family support, however, almost always assigning responsibility toward the adolescents. The predominant feeling due to the precocity of gestation is the conformism
Objetivo: Conhecer as experiências de familiares de adolescentes grávidas assistidas pelas ESF do município de Montes Claros/MG, acerca da gestação precoce. Métodos: Trata-se de um estudo descritivo com abordagem qualitativa, no qual foram entrevistados 10 familiares de adolescentes grávidas. Resultados: Percebe-se com a pesquisa que os familiares referem a sexualidade como ato sexual somente. Os entrevistados relacionam a gestação precoce à vários fatores. A aceitação da gravidez é referida como positiva, mesmo quando inesperada. Conclusão: As condutas adotadas transitam desde o aconselhamento até a oferta de apoio familiar, mas quase sempre designando a responsabilidade para as adolescentes. O sentimento predominante é o de conformismo, devido à precocidade da gestação
Objetivo: Conocer las experiencias de la familia de las adolescentes embarazadas asistidas por municipio Montes del FSE Claros / MG, sobre el embarazo temprano. Metodos: Se realizó un estudio cualitativo descriptivo, que entrevistó a 10 familiares de las adolescentes embarazadas. Resultados: Se percibe a la investigación de la familia se refiere a la sexualidad, ya que sólo el coito. Los encuestados se relacionan con el embarazo temprano a varios factores. La aceptación de embarazo se denomina positiva, incluso cuando inesperado. Conclusion: Las tuberías adoptadas en tránsito desde el asesoramiento para ofrecer apoyo a la familia, pero a menudo la asignación de la responsabilidad de los adolescentes. La sensación predominante es el conformismo, debido a los embarazos precoces
Assuntos
Humanos , Masculino , Feminino , Gravidez , Adolescente , Adulto , Pessoa de Meia-Idade , Saúde do Adolescente , Família/psicologia , Gravidez na Adolescência , Comportamento do AdolescenteRESUMO
Tumor expression of the lymphangiogenic factor VEGF-C is correlated with metastasis and poor prognosis, and although VEGF-C enhances transport to the draining lymph node (dLN) and antigen exposure to the adaptive immune system, its role in tumor immunity remains unexplored. Here, we demonstrate that VEGF-C promotes immune tolerance in murine melanoma. In B16 F10 melanomas expressing a foreign antigen (OVA), VEGF-C protected tumors against preexisting antitumor immunity and promoted local deletion of OVA-specific CD8(+) T cells. Naive OVA-specific CD8(+) T cells, transferred into tumor-bearing mice, were dysfunctionally activated and apoptotic. Lymphatic endothelial cells (LECs) in dLNs cross-presented OVA, and naive LECs scavenge and cross-present OVA in vitro. Cross-presenting LECs drove the proliferation and apoptosis of OVA-specific CD8(+) T cells ex vivo. Our findings introduce a tumor-promoting role for lymphatics in the tumor and dLN and suggest that lymphatic endothelium in the local microenvironment may be a target for immunomodulation.
Assuntos
Antígenos de Neoplasias/imunologia , Apresentação Cruzada/imunologia , Tolerância Imunológica/imunologia , Linfonodos/imunologia , Melanoma Experimental/imunologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Animais , Apresentação de Antígeno/imunologia , Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Células Endoteliais/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Linfonodos/patologia , Linfangiogênese , Melanoma Experimental/patologia , Melanoma Experimental/prevenção & controle , Camundongos , Metástase Neoplásica , Peptídeos/imunologia , Células Estromais/metabolismoRESUMO
The Schistosoma mansoni tegument interaction with the immune system plays a key role in disease establishment or elimination. We have recently demonstrated that S. mansoni schistosomula tegument (Smteg) is able to activate innate immune response and to induce protective immunity in a vaccine formulation with Freunds adjuvant. In this work, we evaluated the ability of Smteg to elicit protection in the absence of adjuvant. Smteg mice immunization resulted in significant antibody production, increased percentage of CD4+IFN-g+ and CD4+IL-10+ cells in spleen and increased production of IFN-g and IL-10 by spleen cells, but failed to reduce parasite burden, female fecundity and morbidity. We also demonstrated that BMDC stimulation with Smteg resulted in significant IL-10 production. Our results demonstrate that Smteg has immune modulatory proprieties.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteínas de Helminto/imunologia , Imunização/métodos , Interleucina-10/metabolismo , Schistosoma mansoni/imunologia , Esquistossomose mansoni/prevenção & controle , Vacinas/imunologia , Animais , Anticorpos Anti-Helmínticos/sangue , Antígenos de Helmintos/administração & dosagem , Antígenos de Helmintos/imunologia , Feminino , Fertilidade/imunologia , Proteínas de Helminto/administração & dosagem , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Carga Parasitária , Vacinas/administração & dosagemRESUMO
Schistosoma mansoni schistosomula are the most susceptible parasite life stage to host immune system attack. Complex host-parasite interactions take place on Schistosoma tegument, which is a unique double membrane structure involved in nutrition and immune evasion. Herein, we have demonstrated that schistosomula tegument (Smteg) activates Dendritic cells to produce IL-12p40, TNF-alpha and also to up-regulate the co-stimulatory molecules CD40 and CD86. Moreover, using DCs derived from MyD88-, TLR2-, TLR4- and TLR9-deficient mice we have shown that the ability of Smteg to activate DCs to produce IL-12 and TNF-alpha involves TLR4/Smteg interaction and MyD88 signaling pathway. Finally, our findings lead us to conclude that TLR4 is a key receptor involved in Smteg induction of pro-inflammatory cytokines.