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1.
PLoS Pathog ; 20(4): e1012191, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38683845

RESUMO

An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a role during the initial stages after T. cruzi infection, restraining the magnitude of CD8+ T cell responses and parasite control. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation, exhaustion and functional markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell immunity. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, preventing increased parasite replication in T. cruzi infected mice adoptively transferred with Treg cells. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.


Assuntos
Antígenos CD , Apirase , Linfócitos T CD8-Positivos , Doença de Chagas , Linfócitos T Reguladores , Trypanosoma cruzi , Animais , Doença de Chagas/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T CD8-Positivos/imunologia , Camundongos , Trypanosoma cruzi/imunologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Apirase/imunologia , Apirase/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
2.
Oncoimmunology ; 12(1): 2261326, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37808403

RESUMO

IL-17 immune responses in cancer are controversial, with both tumor-promoting and tumor-repressing effects observed. To clarify the role of IL-17 signaling in cancer progression, we used syngeneic tumor models from different tissue origins. We found that deficiencies in host IL-17RA or IL-17A/F expression had varying effects on the in vivo growth of different solid tumors including melanoma, sarcoma, lymphoma, and leukemia. In each tumor type, the absence of IL-17 led to changes in the expression of mediators associated with inflammation and metastasis in the tumor microenvironment. Furthermore, IL-17 signaling deficiencies in the hosts resulted in decreased anti-tumor CD8+ T cell immunity and caused tumor-specific changes in several lymphoid cell populations. Our findings were associated with distinct patterns of IL-17A/F cytokine and receptor subunit expression in the injected tumor cell lines. These patterns affected tumor cell responsiveness to IL-17 and downstream intracellular signaling, leading to divergent effects on cancer progression. Additionally, we identified IL-17RC as a critical determinant of the IL-17-mediated response in tumor cells and a potential biomarker for IL-17 signaling effects in tumor progression. Our study offers insight into the molecular mechanisms underlying IL-17 activities in cancer and lays the groundwork for developing personalized immunotherapies.


Assuntos
Neoplasias , Receptores de Interleucina-17 , Humanos , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Interleucina-17 , Transdução de Sinais , Linfócitos T CD8-Positivos , Inflamação , Neoplasias/genética
3.
bioRxiv ; 2023 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-37745571

RESUMO

An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a critical role during the initial stages after T. cruzi infection, subsequently influencing CD8+ T cells. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell responses. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, leading to improved parasite control during T. cruzi infection. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

4.
mBio ; 11(3)2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398312

RESUMO

Treatment with anti-CD20, used in many diseases in which B cells play a pathogenic role, has been associated with susceptibility to intracellular infections. Here, we studied the effect of anti-CD20 injection on CD8+ T cell immunity using an experimental model of Trypanosoma cruzi infection, in which CD8+ T cells play a pivotal role. C57BL/6 mice were treated with anti-CD20 for B cell depletion prior to T. cruzi infection. Infected anti-CD20-treated mice exhibited a CD8+ T cell response with a conserved expansion phase followed by an early contraction, resulting in a strong reduction in total and parasite-specific CD8+ T cell numbers at 20 days postinfection. Anti-CD20 injection increased the frequency of apoptotic CD8+ T cells, decreased the number of effector and memory CD8+ T cells, and reduced the frequency of proliferating and cytokine-producing CD8+ T cells. Accordingly, infected anti-CD20-treated mice presented lower cytotoxicity of T. cruzi peptide-pulsed target cells in vivo All of these alterations in CD8+ T cell immunity were associated with increased tissue parasitism. Anti-CD20 injection also dampened the CD8+ T cell response, when this had already been generated, indicating that B cells were involved in the maintenance rather than the induction of CD8+ T cell immunity. Anti-CD20 injection also resulted in a marked reduction in the frequency of interleukin-6 (IL-6)- and IL-17A-producing cells, and recombinant IL-17A (rIL-17A) injection partially restored the CD8+ T cell response in infected anti-CD20-treated mice. Thus, anti-CD20 reduced CD8+ T cell immunity, and IL-17A is a candidate for rescuing deficient responses either directly or indirectly.IMPORTANCE Monoclonal antibody targeting the CD20 antigen on B cells is used to treat the majority of non-Hodgkin lymphoma patients and some autoimmune disorders. This therapy generates adverse effects, notably opportunistic infections and activation of viruses from latency. Here, using the infection murine model with the intracellular parasite Trypanosoma cruzi, we report that anti-CD20 treatment affects not only B cell responses but also CD8+ T cell responses, representing the most important immune effectors involved in control of intracellular pathogens. Anti-CD20 treatment, directly or indirectly, affects cytotoxic T cell number and function, and this deficient response was rescued by the cytokine IL-17A. The identification of IL-17A as the cytokine capable of reversing the poor response of CD8+ T cells provides information about a potential therapeutic treatment aimed at enhancing defective immunity induced by B cell depletion.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos CD20/imunologia , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Interleucina-17/imunologia , Animais , Anticorpos Monoclonais/imunologia , Doença de Chagas/prevenção & controle , Feminino , Injeções Intraperitoneais , Interleucina-17/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Trypanosoma cruzi
5.
Trends Parasitol ; 35(11): 899-917, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31607632

RESUMO

The protozoan Trypanosoma cruzi is the causative agent of Chagas' disease, endemic in Latin America but present worldwide. Research efforts have focused on the examination of immune mechanisms that mediate host protection as well as immunopathology during this parasitic infection. The study of CD8+ T cell immunity emerges as a key aspect given the critical importance of parasite-specific CD8+ T cells for host resistance throughout the infection. In recent years, new research has shed light on novel pathways that modulate the induction, maintenance, and regulation of CD8+ T cell responses to T. cruzi. This new knowledge is setting the ground for future vaccines and/or immunotherapies. Herein, we critically review and analyze the latest results published in the field.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Interações Hospedeiro-Parasita/imunologia , Trypanosoma cruzi/imunologia , Doença de Chagas/parasitologia , Doença de Chagas/prevenção & controle , Humanos , Pesquisa/tendências
6.
Front Immunol ; 9: 2555, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455700

RESUMO

While it is now acknowledged that CD4+ T cells expressing CD25 and Foxp3 (Treg cells) regulate immune responses and, consequently, influence the pathogenesis of infectious diseases, the regulatory response mediated by Treg cells upon infection by Trypanosoma cruzi was still poorly characterized. In order to understand the role of Treg cells during infection by this protozoan parasite, we determined in time and space the magnitude of the regulatory response and the phenotypic, functional and transcriptional features of the Treg cell population in infected mice. Contrary to the accumulation of Treg cells reported in most chronic infections in mice and humans, experimental T. cruzi infection was characterized by sustained numbers but decreased relative frequency of Treg cells. The reduction in Treg cell frequency resulted from a massive accumulation of effector immune cells, and inversely correlated with the magnitude of the effector immune response as well as with emergence of acute immunopathology. In order to understand the causes underlying the marked reduction in Treg cell frequency, we evaluated the dynamics of the Treg cell population and found a low proliferation rate and limited accrual of peripheral Treg cells during infection. We also observed that Treg cells became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. To assess the biological relevance of the relative reduction in Treg cells frequency observed during T. cruzi infection, we transferred in vitro differentiated Treg cells at early moments, when the deregulation of the ratio between regulatory and conventional T cells becomes significant. Intravenous injection of Treg cells dampened parasite-specific CD8+ T cell immunity and affected parasite control in blood and tissues. Altogether, our results show that limited Treg cell response during the acute phase of T. cruzi infection enables the emergence of protective anti-parasite CD8+ T cell immunity and critically influences host resistance.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/imunologia , Linfócitos T Reguladores/imunologia , Trypanosoma cruzi/imunologia , Transferência Adotiva , Animais , Proliferação de Células , Ativação Linfocitária/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/transplante
7.
Front Immunol ; 9: 2347, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364284

RESUMO

The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms that are not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes, and their survival and ability to mount cytotoxic responses are orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. The absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells, while in vitro recombinant IL-17 down-regulated the pro-apoptotic protein BAD and promoted the survival of activated CD8+ T cells. Phenotypic, functional, and transcriptomic profiling showed that T. cruzi-specific CD8+ T cells derived from IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Doença de Chagas/imunologia , Doença de Chagas/metabolismo , Receptores de Interleucina-17/metabolismo , Transdução de Sinais , Trypanosoma cruzi/imunologia , Transferência Adotiva , Animais , Apoptose , Sobrevivência Celular , Doença de Chagas/microbiologia , Citocinas/metabolismo , Feminino , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunomodulação/genética , Interleucina-17/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Knockout , Receptores de Interleucina-17/deficiência , Transcrição Gênica
8.
Cancer Res ; 78(1): 115-128, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29066514

RESUMO

The ability of CD8+ T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8+ T cells marked by high expression of the immunosuppressive ATP ecto-nucleotidase CD39. The frequency of CD39highCD8+ T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8+ T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39+CD8+ T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39+CD8+ T cells inhibited IFNγ production by responder CD8+ T cells. In specimens from breast cancer and melanoma patients, CD39+CD8+ T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within noninvaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFNγ, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induce CD39 on human CD8+ T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8+ T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8+ T cells, with implications for defining a biomarker of T-cell dysfunction and a target for immunotherapeutic intervention.Significance: The tumor microenvironment elicits a subset of functionally exhausted CD8+ T cells by creating conditions that induce cell surface expression of CD39, an immunosuppressive molecule that can be therapeutically targeted to restore effector T-cell function. Cancer Res; 78(1); 115-28. ©2017 AACR.


Assuntos
Antígenos CD/metabolismo , Apirase/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Feminino , Humanos , Metástase Linfática/imunologia , Metástase Linfática/patologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
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