RESUMO
The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.
RESUMO
Memory CD8+ T cells can be broadly divided into circulating (TCIRCM) and tissue-resident memory T (TRM) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of TCIRCM and TRM cells, particularly across tissues, remains elusive. Here, we utilized an antibody screening platform and machine learning prediction pipeline (InfinityFlow) to profile >200 proteins in TCIRCM and TRM cells in solid organs and barrier locations. High-dimensional analyses revealed unappreciated heterogeneity within TCIRCM and TRM cell lineages across nine different organs after either local or systemic murine infection models. Additionally, we demonstrated the relative effectiveness of strategies allowing for the selective ablation of TCIRCM or TRM populations across organs and identified CD55, KLRG1, CXCR6, and CD38 as stable markers for characterizing memory T cell function during inflammation. Together, these data and analytical framework provide an in-depth resource for memory T cell classification in both steady-state and inflammatory conditions.
Assuntos
Linfócitos T CD8-Positivos , Células T de Memória , Camundongos , Animais , Linhagem da Célula , Memória ImunológicaRESUMO
Tissue-resident memory T cells (TRM cells) provide rapid and superior control of localized infections. While the transcription factor Runx3 is a critical regulator of CD8+ T cell tissue residency, its expression is repressed in CD4+ T cells. Here, we show that, as a direct consequence of this Runx3-deficiency, CD4+ TRM cells lacked the transforming growth factor (TGF)-ß-responsive transcriptional network that underpins the tissue residency of epithelial CD8+ TRM cells. While CD4+ TRM cell formation required Runx1, this, along with the modest expression of Runx3 in CD4+ TRM cells, was insufficient to engage the TGF-ß-driven residency program. Ectopic expression of Runx3 in CD4+ T cells incited this TGF-ß-transcriptional network to promote prolonged survival, decreased tissue egress, a microanatomical redistribution towards epithelial layers and enhanced effector functionality. Thus, our results reveal distinct programming of tissue residency in CD8+ and CD4+ TRM cell subsets that is attributable to divergent Runx3 activity.
Assuntos
Memória Imunológica , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Tissue-resident memory T (TRM) cells provide long-lasting immune protection. One of the key events controlling TRM cell development is the local retention of TRM cell precursors coupled to downregulation of molecules necessary for tissue exit. Sphingosine-1-phosphate receptor 5 (S1PR5) is a migratory receptor with an uncharted function in T cells. Here, we show that S1PR5 plays a critical role in T cell infiltration and emigration from peripheral organs, as well as being specifically downregulated in TRM cells. Consequentially, TRM cell development was selectively impaired upon ectopic expression of S1pr5, whereas loss of S1pr5 enhanced skin TRM cell formation by promoting peripheral T cell sequestration. Importantly, we found that T-bet and ZEB2 were required for S1pr5 induction and that local TGF-ß signaling was necessary to promote coordinated Tbx21, Zeb2, and S1pr5 downregulation. Moreover, S1PR5-mediated control of tissue residency was conserved across innate and adaptive immune compartments. Together, these results identify the T-bet-ZEB2-S1PR5 axis as a previously unappreciated mechanism modulating the generation of tissue-resident lymphocytes.
Assuntos
Diferenciação Celular/genética , Tecido Linfoide/metabolismo , Células T de Memória/metabolismo , Receptores de Esfingosina-1-Fosfato/genética , Linfócitos T/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Movimento Celular/genética , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , RNA-Seq/métodos , Receptores de Esfingosina-1-Fosfato/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismoRESUMO
Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Microambiente Celular/imunologia , Memória Imunológica/imunologia , Animais , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Central memory T (TCM) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (TRM) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated TRM cells rejoined the circulating pool. Epigenetic analyses revealed that TRM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated TRM cells isolated from small intestine epithelium exhibited the potential to differentiate into TCM cells, effector memory T cells and TRM cells on recall. Ex-TRM cells, former intestinal TRM cells that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin on subsequent reactivation and a heightened capacity to redifferentiate into TRM cells. Thus, TRM cells can rejoin the circulation but are advantaged to re-form local TRM when called on.
Assuntos
Plasticidade Celular/imunologia , Memória Imunológica/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular/imunologia , Feminino , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Abstract Objective To evaluate conditions associated with stillbirth (SB), and possible trends related with it, in a maternity hospital school in the North zone of São Paulo. Methods An observational, cross-sectional study conducted at the Hospital Maternidade- escola de Vila Nova Cachoeirinha with 1,139 SBs in the period of 2003 to 2017. Cases of intermediate SB (ISB) (weight between 500 and 999 g) and late SB (LSB) (weight ≥ 1,000 g) were compared. We evaluated clinical data, laboratory tests, and fetal and placental studies. Data were stored in Windows Excel (Microsoft Corp., Redmond, WA, USA) worksheets, according to which graphs and tables were constructed. We used the statistical software SPSS for Windows version 18.0 (SPSS In., Chicago, IL, USA), estimating the prevalence ratio (PR) and odds ratio (OR), considering the 95% confidence interval (95% CI). Results The general SB rate was 11.9%, and the in-hospital SB rate was 2.8%. Pregnant women younger than 16 years of age were more likely to have ISB (OR 0.32, 0.15- 0.76), while patients older than 40 years old had a higher chance of LSB (PR 0.85, 0.72- 0.99). A total of 25.7% of the general population did not have prenatal care, and 77.1% of the cases presented fetal death at admission. The cases of ISB had a statistically significant association with home birth (OR 0.61, 0.46-0.80). Cesarean section was performed in 16.1% of the subjects, and misoprostol was the most used method for induction. Necropsy and placental study of the fetuses were performed, respectively, in 94.2% and 97.3% of the cases. Associated causes were not identified in 22.1% of the cases, and the main causes identified were amniotic sac infections (27.9%), fetal malformations (12.5%), placental abruption (11.2%), hypertensive syndromes (8.5%), and maternal syphilis (3.9%), the latter with an increasing trend. Conclusion Among the factors associated to SB were: hypertensive syndromes, amniotic sac infections, fetal malformations, placental abruption and syphilis. There was a growing trend in the number of cases of syphilis, which translates an alert. Diagnostic limitations justify indeterminate causes.
Resumo Objetivo Avaliar aspectos relacionados à ocorrência da condição de natimortalidade em uma maternidade-escola na zona norte de São Paulo e possíveis tendências associadas aos fatores causais. Métodos Estudo observacional, transversal, realizado no Hospital Maternidadeescola Vila Nova Cachoeirinha com 1.139 óbitos fetais (OF) no período de 2003 a 2017. Foram comparados os casos de OF intermediários (OFI) (peso entre 500 e 999 g) e OF tardios (OFT) (≥ 1,000 g). Avaliamos dados clínicos, exames laboratoriais, e estudos do feto e da placenta; estes foram armazenados em planilhas de Windows Excel (Microsoft Corp., Redmond, WA USA0, utilizando-se para avaliação estatística o programa SPSS v.18 (SPSS Inc., Chicago, IL, EUA). Foram ainda estimadas a razão de prevalência (RP) e a razão de chances (RC), com intervalo de confiança de 95% (IC 95%). Resultados Ocoeficiente de natimortalidade geral foi de 11,9% e o intra-hospitalar foi de 2,8%. Gestantes com menos de 16 anos de idade apresentaram maior chance de ter OFI (RC 0.32, 0.15-0.76) enquanto que pacientes com mais de 40 anos de idade apresentaram maior chance de OFT (RP 0,85; 0,72-0,99). Não fizeram prenatal 25,7% da população geral, sendo que em 77,1% dos casos, a morte fetal já tinha sido apresentada na internação. Os casos de OFI apresentaram associação estatisticamente significante com parto domiciliar (RC 0,42; 0,23-0,75). A cesárea foi realizada em 16,1% das pacientes, sendo o misoprostol o método mais utilizado para indução. Necropsia foi feita em 94,2% dos fetos, e 97,3% das placentas foram para estudo. As causas associadas não foram identificadas em 22,1% dos casos, sendo que as principais causas identificadas foram infecções do saco amniótico e membranas (27,9%), malformações (12,5%), descolamento prematuro de placenta (11,2%), síndromes hipertensivas (8,5%), e sífilis (3,9%), sendo esta última com uma tendência crescente. Conclusão Destacaram-se como fatores associados à natimortalidade: síndromes hipertensivas, corioamnionites, malformações fetais, descolamento placentário e sífilis. Houve tendência de aumento no número de casos de sífilis, o que traduz uma alerta. Limitações diagnósticas justificam as causas indeterminadas.
Assuntos
Humanos , Feminino , Gravidez , Adolescente , Adulto , Adulto Jovem , Natimorto/epidemiologia , Complicações na Gravidez/epidemiologia , Cuidado Pré-Natal/estatística & dados numéricos , Brasil/epidemiologia , Estudos Transversais , Gravidez de Alto Risco , Maternidades , Hospitais de EnsinoRESUMO
OBJECTIVE: To evaluate conditions associated with stillbirth (SB), and possible trends related with it, in a maternity hospital school in the North zone of São Paulo. METHODS: An observational, cross-sectional study conducted at the Hospital Maternidade-escola de Vila Nova Cachoeirinha with 1,139 SBs in the period of 2003 to 2017. Cases of intermediate SB (ISB) (weight between 500 and 999 g) and late SB (LSB) (weight ≥ 1,000 g) were compared. We evaluated clinical data, laboratory tests, and fetal and placental studies. Data were stored in Windows Excel (Microsoft Corp., Redmond, WA, USA) worksheets, according to which graphs and tables were constructed. We used the statistical software SPSS for Windows version 18.0 (SPSS In., Chicago, IL, USA), estimating the prevalence ratio (PR) and odds ratio (OR), considering the 95% confidence interval (95% CI). RESULTS: The general SB rate was 11.9%, and the in-hospital SB rate was 2.8%. Pregnant women younger than 16 years of age were more likely to have ISB (OR 0.32, 0.15-0.76), while patients older than 40 years old had a higher chance of LSB (PR 0.85, 0.72-0.99). A total of 25.7% of the general population did not have prenatal care, and 77.1% of the cases presented fetal death at admission. The cases of ISB had a statistically significant association with home birth (OR 0.61, 0.46-0.80). Cesarean section was performed in 16.1% of the subjects, and misoprostol was the most used method for induction. Necropsy and placental study of the fetuses were performed, respectively, in 94.2% and 97.3% of the cases. Associated causes were not identified in 22.1% of the cases, and the main causes identified were amniotic sac infections (27.9%), fetal malformations (12.5%), placental abruption (11.2%), hypertensive syndromes (8.5%), and maternal syphilis (3.9%), the latter with an increasing trend. CONCLUSION: Among the factors associated to SB were: hypertensive syndromes, amniotic sac infections, fetal malformations, placental abruption and syphilis. There was a growing trend in the number of cases of syphilis, which translates an alert. Diagnostic limitations justify indeterminate causes.
OBJETIVO: Avaliar aspectos relacionados à ocorrência da condição de natimortalidade em uma maternidade-escola na zona norte de São Paulo e possíveis tendências associadas aos fatores causais. MéTODOS: Estudo observacional, transversal, realizado no Hospital Maternidade-escola Vila Nova Cachoeirinha com 1.139 óbitos fetais (OF) no período de 2003 a 2017. Foram comparados os casos de OF intermediários (OFI) (peso entre 500 e 999 g) e OF tardios (OFT) (≥ 1,000 g). Avaliamos dados clínicos, exames laboratoriais, e estudos do feto e da placenta; estes foram armazenados em planilhas de Windows Excel (Microsoft Corp., Redmond, WA USA0, utilizando-se para avaliação estatística o programa SPSS v.18 (SPSS Inc., Chicago, IL, EUA). Foram ainda estimadas a razão de prevalência (RP) e a razão de chances (RC), com intervalo de confiança de 95% (IC 95%). RESULTADOS: O coeficiente de natimortalidade geral foi de 11,9% e o intra-hospitalar foi de 2,8%. Gestantes com menos de 16 anos de idade apresentaram maior chance de ter OFI (RC 0.32, 0.150.76) enquanto que pacientes com mais de 40 anos de idade apresentaram maior chance de OFT (RP 0,85; 0,720,99). Não fizeram prenatal 25,7% da população geral, sendo que em 77,1% dos casos, a morte fetal já tinha sido apresentada na internação. Os casos de OFI apresentaram associação estatisticamente significante com parto domiciliar (RC 0,42; 0,230,75). A cesárea foi realizada em 16,1% das pacientes, sendo o misoprostol o método mais utilizado para indução. Necropsia foi feita em 94,2% dos fetos, e 97,3% das placentas foram para estudo. As causas associadas não foram identificadas em 22,1% dos casos, sendo que as principais causas identificadas foram infecções do saco amniótico e membranas (27,9%), malformações (12,5%), descolamento prematuro de placenta (11,2%), síndromes hipertensivas (8,5%), e sífilis (3,9%), sendo esta última com uma tendência crescente. CONCLUSãO: Destacaram-se como fatores associados à natimortalidade: síndromes hipertensivas, corioamnionites, malformações fetais, descolamento placentário e sífilis. Houve tendência de aumento no número de casos de sífilis, o que traduz uma alerta. Limitações diagnósticas justificam as causas indeterminadas.
Assuntos
Natimorto/epidemiologia , Adolescente , Adulto , Brasil/epidemiologia , Estudos Transversais , Feminino , Maternidades , Hospitais de Ensino , Humanos , Gravidez , Complicações na Gravidez/epidemiologia , Gravidez de Alto Risco , Cuidado Pré-Natal/estatística & dados numéricos , Adulto JovemRESUMO
Cardiomyopathy is the most serious consequence of Chagas disease, a neglected human disorder caused by Trypanosoma cruzi infection. Because T. cruzi parasites invade cardiomyocytes, we sought to investigate whether these cells recognize the parasite in vivo by receptors signaling through the MyD88 adaptor, which mediates the activation pathway of most Toll-like receptors (TLRs) and IL-1/IL-18 receptors, and influence the development of acute cardiac pathology. First, we showed that HL-1 cardiac muscle cell line expresses MyD88 gene and protein at resting state and after T. cruzi infection. To evaluate the role in vivo of MyD88 expression in cardiomyocytes, we generated Mer+MyD88flox+/+ mice in which tamoxifen treatment is expected to eliminate the MyD88 gene exclusively in cardiomyocytes. This Cre-loxP model was validated by both PCR and western blot analysis; tamoxifen treatment of Mer+MyD88flox+/+ mice resulted in decreased MyD88 gene and protein expression in the heart, but not in the spleen, while had no effect on littermates. The elimination of MyD88 in cardiomyocytes determined a lower increase in CCL5, IFNγ and TNFα gene transcription during acute infection by T. cruzi parasites of the Y strain, but it did not significantly modify heart leukocyte infiltration and parasitism. Together, our results show that cardiomyocytes can sense T. cruzi infection through MyD88-mediated molecular pathways and contribute to the local immune response to the parasite. The strong pro-inflammatory response of heart-recruited leukocytes may overshadow the effects of MyD88 deficiency in cardiomyocytes on the local leukocyte recruitment and T. cruzi control during acute infection.
Assuntos
Cardiomiopatia Chagásica/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Miócitos Cardíacos/metabolismo , Trypanosoma cruzi/imunologia , Animais , Linhagem Celular , Cardiomiopatia Chagásica/metabolismo , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Humanos , Camundongos Knockout , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/genética , Miocárdio/imunologia , Miocárdio/metabolismo , RNA Mensageiro , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologiaRESUMO
Extracellular ATP (eATP) is an ancient 'danger signal' used by eukaryotes to detect cellular damage1. In mice and humans, the release of eATP during inflammation or injury stimulates both innate immune activation and chronic pain through the purinergic receptor P2RX72-4. It is unclear, however, whether this pathway influences the generation of immunological memory, a hallmark of the adaptive immune system that constitutes the basis of vaccines and protective immunity against re-infection5,6. Here we show that P2RX7 is required for the establishment, maintenance and functionality of long-lived central and tissue-resident memory CD8+ T cell populations in mice. By contrast, P2RX7 is not required for the generation of short-lived effector CD8+ T cells. Mechanistically, P2RX7 promotes mitochondrial homeostasis and metabolic function in differentiating memory CD8+ T cells, at least in part by inducing AMP-activated protein kinase. Pharmacological inhibitors of P2RX7 provoked dysregulated metabolism and differentiation of activated mouse and human CD8+ T cells in vitro, and transient P2RX7 blockade in vivo ameliorated neuropathic pain but also compromised production of CD8+ memory T cells. These findings show that activation of P2RX7 by eATP provides a common currency that both alerts the nervous and immune system to tissue damage, and promotes the metabolic fitness and survival of the most durable and functionally relevant memory CD8+ T cell populations.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica , Receptores Purinérgicos P2X7/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Ativação Enzimática , Feminino , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Receptores Purinérgicos P2X7/deficiência , Receptores Purinérgicos P2X7/genéticaRESUMO
Chagas disease is a neglected parasitic infection that affects around six to seven million people, mainly in Latin America. About 30-35% of infected people present chronic Chagas cardiomyopathy (CCC), which eventually leads to death. This condition is characterized by local parasite persistence and leukocyte infiltration. In a murine model of CCC, we observed that among infiltrating leukocytes, CD4+ and CD8+ T cells were in higher frequency in the heart of chronically infected mice, although elevated expression of the regulatory molecules programmed cell death protein 1 (PD1) and PDL1 suggested these cells could be inhibited. To investigate if PD1-PDL1 interaction in the heart of chronically infected mice negatively impacts on the local immune response, facilitating parasite persistence, and progression to CCC, we attempted to recover the local immune response by treating chronically infected mice with anti-PD1 and anti-PDL1-blocking antibodies together with irradiated Trypanosoma cruzi, which provides immune response boosting. Irradiated parasites promote expression of costimulatory molecules in dendritic cells and provide specific parasite antigen, which should aid T cell reactivation upon checkpoint blockade. Following treatment, there was an increased frequency of heart-infiltrating CD4+ and CD8+ T cells with an effector memory phenotype, an increased histopathology score and decreased heart rate, supporting our previous hypothesis of local immunosuppression induced by this pathway during CCC. In addition, blood parasitemia was reduced, which was associated with increased T. cruzi-specific immunoglobulin G 1 antibodies. However, no difference was observed in cytokine production or T. cruzi burden in the hearts of treated mice. Taken together, our results suggest PD1-PDL1 interaction protects the heart from excessive immune response.
Assuntos
Antígeno B7-H1/metabolismo , Cardiomiopatia Chagásica/prevenção & controle , Traumatismos Cardíacos/prevenção & controle , Receptor de Morte Celular Programada 1/metabolismo , Animais , Antígeno B7-H1/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/complicações , Doença de Chagas/imunologia , Modelos Animais de Doenças , Feminino , Traumatismos Cardíacos/parasitologia , Ativação Linfocitária/imunologia , Camundongos , Receptor de Morte Celular Programada 1/genética , Trypanosoma cruzi/imunologiaRESUMO
CD8+ T cell immunosurveillance dynamics influence the outcome of intracellular infections and cancer. Here we used two-photon intravital microscopy to visualize the responses of CD8+ resident memory T cells (TRM cells) within the reproductive tracts of live female mice. We found that mucosal TRM cells were highly motile, but paused and underwent in situ division after local antigen challenge. TRM cell reactivation triggered the recruitment of recirculating memory T cells that underwent antigen-independent TRM cell differentiation in situ. However, the proliferation of pre-existing TRM cells dominated the local mucosal recall response and contributed most substantially to the boosted secondary TRM cell population. We observed similar results in skin. Thus, TRM cells can autonomously regulate the expansion of local immunosurveillance independently of central memory or proliferation in lymphoid tissue.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas/imunologia , Memória Imunológica/imunologia , Vigilância Imunológica/imunologia , Mucosa/imunologia , Animais , Feminino , Microscopia Intravital , Camundongos , Mucosa/citologia , Pele/imunologiaRESUMO
Although it has been established that effector memory CD4(+) T cells play an important role in the protective immunity against chronic infections, little is known about the exact mechanisms responsible for their functioning and maintenance, as well as their effects on innate immune cells. Here we review recent data on the role of IFN-γ priming as a mechanism affecting both innate immune cells and effector memory CD4(+) T cells. Suboptimal concentrations of IFN-γ are seemingly crucial for the optimization of innate immune cell functions (including phagocytosis and destruction of reminiscent pathogens), as well as for the survival and functioning of effector memory CD4(+) T cells. Thus, IFN-γ priming can thus be considered an important bridge between innate and adaptive immunity.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Doenças Transmissíveis/imunologia , Memória Imunológica , Interferon gama/imunologia , Fagócitos/imunologia , Imunidade Adaptativa , Humanos , Imunidade InataRESUMO
The spleen is one of the major immunological sites for maintaining blood homeostasis. Previous studies showed that heterogeneous splenic macrophage populations contribute in complimentary ways to control blood-borne infections and induce effective immune responses. Marginal metallophilic macrophages (MMMΦs) and marginal zone macrophages (MZMΦs) are cells with great ability to internalize blood-borne pathogens such as virus or bacteria. Their localization adjacent to T- and B-cell-rich splenic areas favors the rapid contact between these macrophages and cells from adaptive immunity. Indeed, MMMΦs and MZMΦs are considered important bridges between innate and adaptive immunity. Although red pulp macrophages (RpMΦs) are mainly considered scavengers for senescent erythrocytes, several data indicate a role for RpMΦs in control of infections such as blood-stage malaria as well as in the induction of innate and adaptive immunity. Here, we review current data on how different macrophage subsets recognize and help eliminate blood-borne pathogens, and, in turn, how the inflammatory microenvironment in different phases of infection (acute, chronic, and after pathogen clearance) influences macrophage function and survival.
RESUMO
Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Malária/imunologia , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Imunofluorescência , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Parasitemia/imunologia , Fagocitose/imunologia , Plasmodium chabaudi , Baço/imunologia , Baço/parasitologiaRESUMO
Over the past 20 years, the immune effector mechanisms involved in the control of Trypanosoma cruzi, as well as the receptors participating in parasite recognition by cells of the innate immune system, have been largely described. However, the main questions on the physiopathology of Chagas disease remain unanswered: "Why does the host immune system fail to provide sterile immunity?" and "Why do only a proportion of infected individuals develop chronic pathology?" In this review, we describe the mechanisms proposed to explain the inability of the immune system to eradicate the parasite and the elements that allow the development of chronic heart disease. Moreover, we discuss the possibility that the inability of infected cardiomyocytes to sense intracellular T. cruzi contributes to parasite persistence in the heart and the development of chronic pathology.
Assuntos
Doença de Chagas/imunologia , Animais , Doença de Chagas/complicações , Cardiopatias/etiologia , Cardiopatias/imunologia , Cardiopatias/parasitologia , Humanos , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/parasitologia , Trypanosoma cruzi/imunologia , Trypanosoma cruzi/patogenicidadeRESUMO
Objetivo: uma revisão sistemática da literatura acerca da importância e evolução da autonomia dopaciente como princípio bioético, em respeito ao processo de cidadania. Método: realizado umcriterioso levantamento bibliográfico, a partir de trabalhos publicados na base de dados LILACS eem livros sobre o tema. Atualização/revisão: derivada do grego: Autos = próprio; Nomos = norma,a autonomia pressupõe que a pessoa deve ser livre de coações para que possa escolher a alternativaque melhor lhe convém, podendo sofrer mudanças decorrentes de fatores como a idade ou doenças.A autonomia materializa-se no consentimento livre e esclarecido, que decorre do direito da pessoaconsentir ou recusar propostas de caráter preventivo, diagnóstico ou terapêutico que afetem ouvenham a afetar sua integridade físico-psíquico-social. Considerações finais: o princípio daautonomia rompeu com o antigo conceito paternalista de medicina, no qual o médico era a únicaparte da relação que detinha o poder de decisão, bem como determinava o tratamento que opaciente deveria realizar. No Brasil, este princípio ganhou importância, sendo incorporado aoCódigo de Ética Médica do ano de 2010.
Purpose: to accomplish a systematic review of the literature about the importance and evolution ofpatient autonomy as a bioethical principle, in regard to the citizenship process. Methods: to thisend, the authors conducted a search of scientific articles published on Lilacs and books, related toethics, bioethics and deontology. Literature review: Derived from Greek autos = self, nomos =rule, autonomy presupposes that the person should be free of constraints so that can choose thealternative that best suits, and may be restricted due to factors such as age or illness. The autonomymaterializes in the free and informed consent, which derives from the right of the person to consentor to refuse preventive, diagnostic or therapeutic proposals that affects or will affect their physical,psychological and social integrity. Conclusion: the autonomy principle broke with the ancientconcept of paternalistic medicine, which the doctor was the only part of the relationship that hadthe power to decide and determine the treatment that the patient should make. In Brazil, thisprinciple has gained importance and was incorporated in the Medical Ethics Code of 2010.