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1.
APMIS ; 128(11): 583-592, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32865844

RESUMO

Multiple sclerosis (MS) is an immune-mediated inflammatory disease which affects the central nervous system (CNS). In the present study, the in vivo effects of ATRA, calcitriol, and their combinations on the expression of murine CD4+ T cell cytokines and their specific transcription factors in experimental autoimmune encephalomyelitis (EAE)-induced mice were explored. Thirty-two EAE induced inbred C57BL/6 female mice with an age ranged from 8 to 10 weeks were divided into four categories in a random manner. The first, second, and third groups received ATRA, calcitriol, ATRA+ calcitriol, respectively, and the fourth group received vehicle. The treatment started on the day prior to immunization and through the IP injections every other days for 21 days. The dosages of administration for calcitriol, ATRA, and calcitriol+ ATRA were 100 ng, 250 µg, and 50ng + 125 µg, respectively per mouse. An equal volume of excipient was administered for the vehicle group. T-bet, IFN-γ, GATA-3, and IL-4 genes expression were assessed in the splenocytes of EAE -induced mice. The expression of T-bet and IFN-γ genes in the splenocytes of ATRA, calcitriol and combination- treated mice were significantly reduced compared to vehicle group (p < 0.05). A significant decrease in T-bet expression was observed in the combination-treated group compared to the ATRA-treated group (p < 0.05). The expression of GATA3 and IL-4 genes was significantly increased in the ATRA-, calcitriol-, and combination-treated mice when compared with the control group (p < 0.05). Furthermore, the effect of calcitriol alone and in combination with ATRA was more considerable than that of ATRA alone. The nutraceutical approaches may be promising in the prevention and/or treatment of MS.


Assuntos
Calcitriol/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Tretinoína/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Esquema de Medicação , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia
2.
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
3.
Immunity ; 52(5): 842-855.e6, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32353250

RESUMO

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet+ and T-bet- memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet- and T-bet+ hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet- and T-bet+ MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet+ MBCs could be subdivided into recirculating T-betlo MBCs and spleen-resident T-bethi MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.


Assuntos
Especificidade de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Memória Imunológica/imunologia , Especificidade de Órgãos/imunologia , Proteínas com Domínio T/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Anticorpos Anti-HIV/imunologia , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Influenza Humana/virologia , Camundongos , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
4.
Immunity ; 52(5): 825-841.e8, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32396847

RESUMO

CD8+ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8+ T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1+ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Transcrição Genética/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Epigênese Genética/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/terapia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcrição Genética/genética
5.
PLoS Biol ; 18(3): e3000648, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32182234

RESUMO

The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.


Assuntos
Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Proteínas com Domínio T/imunologia , Animais , Variação Antigênica/imunologia , Sobrevivência Celular/imunologia , Células Cultivadas , Seleção Clonal Mediada por Antígeno/genética , Seleção Clonal Mediada por Antígeno/imunologia , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária , Camundongos , Células Precursoras de Linfócitos T/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Proteínas com Domínio T/genética
6.
J Immunol ; 204(5): 1373-1385, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31969386

RESUMO

Adoptive cellular therapy and its derivative, chimeric AgR T cell therapy, have achieved significant progress against cancer. Major barriers persist, however, including insufficient induction of cytotoxic T cells and exhaustion of tumor-infiltrating lymphocytes. In this study, we discovered a new role for 2-deoxy-d-glucose (2DG) in enhancing the antitumor activity of human T cells against NKG2D ligand-expressing tumor cells. Human T cells treated with 2DG upregulated the NK-specific transcription factors TOX2 and EOMES, thereby acquiring NK cell properties, including high levels of perforin/granzyme and increased sensitivity to IL-2. Notably, rather than inhibiting glycolysis, 2DG modified N-glycosylation, which augmented antitumor activity and cell surface retention of IL-2R of T cells. Moreover, 2DG treatment prevented T cells from binding to galectin-3, a potent tumor Ag associated with T cell anergy. Our results, therefore, suggest that modifying N-glycosylation of T cells with 2DG could improve the efficacy of T cell-based immunotherapies against cancer.


Assuntos
Desoxiglucose/farmacologia , Imunidade Celular/efeitos dos fármacos , Neoplasias/imunologia , Linfócitos T/imunologia , Glicosilação/efeitos dos fármacos , Proteínas HMGB/imunologia , Humanos , Imunoterapia , Interleucina-2/imunologia , Células K562 , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Proteínas com Domínio T/imunologia , Linfócitos T/patologia
7.
Cancer Immunol Res ; 8(3): 321-333, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31964625

RESUMO

CD8+ T cells can be polarized into several different subsets as defined by the cytokines they produce and the transcription factors that govern their differentiation. Here, we identified the polarizing conditions to induce an IL22-producing CD8+ Tc22 subset, which is dependent on IL6 and the aryl hydrocarbon receptor transcription factor. Further characterization showed that this subset was highly cytolytic and expressed a distinct cytokine profile and transcriptome relative to other subsets. In addition, polarized Tc22 were able to control tumor growth as well as, if not better than, the traditional IFNγ-producing Tc1 subset. Tc22s were also found to infiltrate the tumors of human patients with ovarian cancer, comprising up to approximately 30% of expanded CD8+ tumor-infiltrating lymphocytes (TIL). Importantly, IL22 production in these CD8+ TILs correlated with improved recurrence-free survival. Given the antitumor properties of Tc22 cells, it may be prudent to polarize T cells to the Tc22 lineage when using chimeric antigen receptor (CAR)-T or T-cell receptor (TCR) transduction-based immunotherapies.


Assuntos
Imunoterapia Adotiva/métodos , Interleucina-6/farmacologia , Interleucinas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/terapia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Polaridade Celular/imunologia , Feminino , Humanos , Interleucina-6/biossíntese , Interleucina-6/genética , Interleucina-6/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Hidrocarboneto Arílico/imunologia , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma , Células Tumorais Cultivadas
8.
Br J Haematol ; 189(1): 133-145, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31724172

RESUMO

Chronic lymphocytic leukaemia (CLL) is associated with alterations in T cell number, subset distribution and function. Among these changes, an increase in CD4+ T cells was reported. CD4+ T cells are a heterogeneous population and distinct subsets have been described to exert pro- and anti-tumour functions. In CLL, controversial reports describing the dominance of IFNγ-expressing Th1 T cells or of IL-4-producing Th2 T cells exist. Our study shows that blood of CLL patients is enriched in Th1 T cells producing high amounts of IFNγ. Moreover, we observed that their frequency remains relatively stable in CLL patients over a time course of five years. Furthermore, we provide evidence for an accumulation of Th1 T cells in the Eµ-TCL1 mouse model of CLL. As TBET (encoded by Tbx21) is a crucial transcription factor for Th1 polarization, we generated Tbx21-/- bone marrow chimaeric mice which showed a lower number of IFNγ-producing Th1 T cells, and used them for adoptive transfer of Eµ-TCL1 leukaemia. Disease development in these mice was, however, comparable to that in wild-type controls, excluding a major role for TBET-expressing Th1 cells in Eµ-TCL1 leukaemia. Collectively, our data highlight that Th1 T cells accumulate in CLL but reducing their number has no impact on disease development.


Assuntos
Regulação Leucêmica da Expressão Gênica/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Proteínas com Domínio T/imunologia , Células Th1/imunologia , Animais , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas com Domínio T/genética , Células Th1/patologia
9.
Mol Immunol ; 118: 30-39, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31841965

RESUMO

The imbalance of helper T cell (Th) 1/Th2 differentiation is involved in the development of allergic rhinitis (AR). Recent studies reveal the regulatory function of exosomes on Th1/Th2 differentiation. However, the key mediator in exosomes that modulate such response remains unclear. In this study, the expression of long-noncoding RNA GAS5 (LncGAS5) was detected in exosomes which were isolated from AR patient nasal mucus (AR-EXO) and ovalbumin (OVA)-stimulated nasal epithelial cells (OVA-EXO). Th1/Th2 differentiation was induced in naïve CD4+ T cells, and the percentage of IFN-γ expressing cells (Th1 cells) and IL-4 expressing cells (Th2 cells) was detected using flow cytometry. The result showed that LncGAS5 was upregulated in AR epithelial samples, AR-EXO, and OVA-EXO. The coincubation of AR-EXO and CD4+ T cells suppressed Th1 differentiation and promoted Th2 differentiation, which is mediated by LncGAS5 in AR-EXO. The LncGAS5 in AR-EXO inhibited transcription and expression of EZH2, and it also inhibited T-bet expression at mRNA and protein levels. The gain-of-function and loss-of-function experiments suggested that LncGAS5 mediates Th1/Th2 differentiation partly through downregulating T-bet and EZH2. In summary, our findings demonstrated that LncGAS5 in AR epithelium-derived exosomes is the key mediator in Th1/Th2 differentiation, providing a possible therapeutic target of AR.


Assuntos
Regulação para Baixo/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , RNA Longo não Codificante/imunologia , Rinite Alérgica/imunologia , Proteínas com Domínio T/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Citocinas/imunologia , Células Epiteliais/imunologia , Exossomos/imunologia , Feminino , Humanos , Masculino , Mucosa Nasal/imunologia , Equilíbrio Th1-Th2/fisiologia , Transcrição Genética/imunologia , Regulação para Cima/imunologia
10.
Proc Natl Acad Sci U S A ; 116(49): 24760-24769, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31740609

RESUMO

Intestinal innate lymphoid cells (ILCs) contribute to the protective immunity and homeostasis of the gut, and the microbiota are critically involved in shaping ILC function. However, the role of the gut microbiota in regulating ILC development and maintenance still remains elusive. Here, we identified opposing effects on ILCs by two Helicobacter species, Helicobacter apodemus and Helicobacter typhlonius, isolated from immunocompromised mice. We demonstrated that the introduction of both Helicobacter species activated ILCs and induced gut inflammation; however, these Helicobacter species negatively regulated RORγt+ group 3 ILCs (ILC3s), especially T-bet+ ILC3s, and diminished their proliferative capacity. Thus, these findings underscore a previously unknown dichotomous regulation of ILC3s by Helicobacter species, and may serve as a model for further investigations to elucidate the host-microbe interactions that critically sustain the maintenance of intestinal ILC3s.


Assuntos
Colite/imunologia , Infecções por Enterobacteriaceae/imunologia , Microbioma Gastrointestinal/imunologia , Helicobacter/imunologia , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Animais , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Colite/induzido quimicamente , Colite/microbiologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/microbiologia , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Tolerância Imunológica , Imunidade Inata , Imunidade nas Mucosas , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Linfócitos/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo
11.
Proc Natl Acad Sci U S A ; 116(42): 21131-21139, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31570595

RESUMO

Induction of eomesodermin-positive CD4+ T cells (Eomes+ T helper [Th] cells) has recently been correlated with the transition from an acute stage to a later stage of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Moreover, these cells' pathogenic role has been experimentally proven in EAE. While exploring how the pathogenic Eomes+ Th cells are generated during the course of EAE, we unexpectedly found that B cells and MHC class II+ myeloid cells isolated from the late EAE lesions strikingly up-regulated the expression of prolactin (PRL). We demonstrate that such PRL-producing cells have a unique potential to induce Eomes+ Th cells from naïve T cells ex vivo, and that anti-MHC class II antibody could block this process. Furthermore, PRL levels in the cerebrospinal fluid were significantly increased in the late phase of EAE, and blocking the production of PRL by bromocriptine or Zbtb20-specific siRNA significantly reduced the numbers of Eomes+ Th cells in the central nervous system (CNS) and ameliorated clinical signs in the later phase of EAE. The PRL dependency of Eomes+ Th cells was confirmed in a series of in vitro and ex vivo experiments. Collectively, these results indicate that extrapituitary PRL plays a crucial role in the CNS inflammation mediated by pathogenic Eomes+ Th cells. Cellular interactions involving PRL-producing immune cells could be considered as a therapeutic target for the prevention of chronic neuroinflammation.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Sistema Nervoso Central/imunologia , Inflamação/imunologia , Prolactina/imunologia , Proteínas com Domínio T/imunologia , Animais , Linfócitos B/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Células Mieloides/imunologia
12.
Front Immunol ; 10: 2158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572375

RESUMO

In normal conditions gut homeostasis is maintained by the suppressive activity of regulatory T cells (Tregs), characterized by the expression of the transcription factor FoxP3. In human inflammatory bowel disease, which is believed to be the consequence of the loss of tolerance toward antigens normally contained in the gut lumen, Tregs have been found to be increased and functionally active, thus pointing against their possible role in the pathogenesis of this immune-mediated disease. Though, in inflammatory conditions, Tregs have been shown to upregulate the T helper (Th) type 1-related transcription factor Tbet and to express the pro-inflammatory cytokine IFNγ, thus suggesting that at a certain point of the inflammatory process, Tregs might contribute to inflammation rather than suppress it. Starting from the observation that Tregs isolated from the lamina propria of active but not inactive IBD patients or uninflamed controls express Tbet and IFNγ, we investigated the functional role of Th1-like Tregs in the dextran sulfate model of colitis. As observed in human IBD, Th1-like Tregs were upregulated in the inflamed lamina propria of treated mice and the expression of Tbet and IFNγ in Tregs preceded the accumulation of conventional Th1 cells. By using a Treg-specific Tbet conditional knockout, we demonstrated that Tbet expression in Tregs is required for the development of colitis. Indeed, Tbet knockout mice developed milder colitis and showed an impaired Th1 immune response. In these mice not only the Tbet deficient Tregs but also the Tbet proficient conventional T cells showed reduced IFNγ expression. However, Tbet deficiency did not affect the Tregs suppressive capacity in vitro and in vivo in the adoptive transfer model of colitis. In conclusion here we show that Tbet expression by Tregs sustains the early phase of the Th1-mediated inflammatory response in the gut.


Assuntos
Colite/imunologia , Regulação da Expressão Gênica/imunologia , Doenças Inflamatórias Intestinais/imunologia , Proteínas com Domínio T/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Animais , Colite/patologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/patologia , Masculino , Camundongos , Linfócitos T Reguladores/patologia , Células Th1/patologia
13.
PLoS One ; 14(7): e0219122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31295271

RESUMO

Exposure to air pollution particulate matter (PM) and tuberculosis (TB) are two of the leading global public health challenges affecting low and middle income countries. An estimated 4.26 million premature deaths are attributable to household air pollution and an additional 4.1 million to outdoor air pollution annually. Mycobacterium tuberculosis (M.tb) infects a large proportion of the world's population with the risk for TB development increasing during immunosuppressing conditions. There is strong evidence that such immunosuppressive conditions develop during household air pollution exposure, which increases rates of TB development. Exposure to urban air pollution has been shown to alter the outcome of TB therapy. Here we examined whether in vitro exposure to urban air pollution PM alters human immune responses to M.tb. PM2.5 and PM10 (aerodynamic diameters <2.5µm, <10µm) were collected monthly from rainy, cold-dry and warm-dry seasons in Iztapalapa, a highly populated TB-endemic municipality of Mexico City with elevated outdoor air pollution levels. We evaluated the effects of seasonality and size of PM on cytotoxicity and antimycobacterial host immunity in human peripheral blood mononuclear cells (PBMC) from interferon gamma (IFN-γ) release assay (IGRA)+ and IGRA- healthy study subjects. PM10 from cold-dry and warm-dry seasons induced the highest cytotoxicity in PBMC. With the exception of PM2.5 from the cold-dry season, pre-exposure to all seasonal PM reduced M.tb phagocytosis by PBMC. Furthermore, M.tb-induced IFN-γ production was suppressed in PM2.5 and PM10-pre-exposed PBMC from IGRA+ subjects. This observation coincides with the reduced expression of M.tb-induced T-bet, a transcription factor regulating IFN-γ expression in T cells. Pre-exposure to PM10 compared to PM2.5 led to greater loss of M.tb growth control. Exposure to PM2.5 and PM10 collected in different seasons differentially impairs M.tb-induced human host immunity, suggesting biological mechanisms underlying altered M.tb infection and TB treatment outcomes during air pollution exposures.


Assuntos
Poluentes Atmosféricos/toxicidade , Citotoxicidade Imunológica/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Material Particulado/toxicidade , Adolescente , Adulto , Idoso , Cidades , Exposição Ambiental/efeitos adversos , Feminino , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Técnicas In Vitro , Interferon gama/biossíntese , Interleucina-1beta/biossíntese , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Masculino , México , Pessoa de Meia-Idade , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tamanho da Partícula , Fagocitose/efeitos dos fármacos , Estações do Ano , Proteínas com Domínio T/imunologia , Saúde da População Urbana , Adulto Jovem
14.
Pediatr Hematol Oncol ; 36(4): 198-210, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31287345

RESUMO

The pathogenesis of aplastic anemia (AA) in children is not clear. This study was conducted to investigate the changes in the proportion and function of regulatory T cells (Tregs) in pediatric AA. The proportion of Tregs, mRNA levels of transcription factors, and concentrations of cytokines were measured by flow cytometry, reverse transcription-PCR, and enzyme-linked immunosorbent assay, respectively. Tregs were co-cultured with effector T cells (Teff) to evaluate the function of Tregs. The proportion of Tregs after immunosuppressive therapy (IST) in pediatric AA was monitored dynamically. Compared to the control, the proportions of Tregs in peripheral blood and bone marrow lymphocytes of the untreated AA group were lower (1.31% ± 0.73% vs. 3.16% ± 0.92%, 1.49% ± 0.81% vs. 3.06% ± 0.82%, respectively, p < 0.001). The mRNA levels of FOXP3 and STAT3 in the AA group were lower (p = 0.014; p < 0.001). However, the mRNA levels of T-BET did not significantly differ between groups. The concentration of interferon-γ and interleukin-17 in the AA group were higher (p = 0.004; p = 0.003), whereas the concentration of TGF-ß decreased (p = 0.044). The immunosuppressive function of Tregs was impaired in the AA group. After IST, the proportion of Tregs was significantly lower than that in the control. The proportion of Tregs at the time of diagnosis in the nonresponsive group was lower than that in the responsive group, but the difference was not significant. Treg levels were significantly decreased and were functionally impaired at the time of diagnosis of pediatric AA. However, there was no significant change in Tregs at the resolution of AA.


Assuntos
Anemia Aplástica/imunologia , Células da Medula Óssea/imunologia , Linfócitos T Reguladores/imunologia , Anemia Aplástica/patologia , Células da Medula Óssea/patologia , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Masculino , Proteínas de Neoplasias/imunologia , RNA Mensageiro/imunologia , Fator de Transcrição STAT3/imunologia , Proteínas com Domínio T/imunologia , Linfócitos T Reguladores/patologia
15.
Eur J Immunol ; 49(11): 2063-2073, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31350760

RESUMO

The role of redox regulation in immune-mediated arthritis has been previously described. However, the relationship between innate immune cells, including innate lymphoid cells (ILCs) and phagocyte-derived ROS, in this process remains unclear. Here, we characterize ILCs and measure the IL-1 family cytokines along with other cytokines relevant to ILC functions and development in serum-induced arthritic joints in wild type and phagocytic NADPH oxidase (NOX2)-deficient Ncf1-/- mice. We found more severe serum-induced joint inflammation and increased NCR+ ILC3s in inflamed joints of Ncf1-/- mice. Furthermore, in vitro stimulation with IL-1ß on Tbet+ ILC1s from joints facilitated their differentiation into ROR-γt+ ILC3s. Moreover, treatment with IL-1 antagonists effectively lowered the proportions of NCR+ ILC3s and IL-17A producing ILC3s in Ncf1-/- arthritic mice and ameliorated the joint inflammation. These results suggest that NOX2 is an essential regulator of ILC transdifferentiation and may mediate this process in a redox-dependent manner through IL-1ß production in the inflammatory joint. Our findings shed important light on the role of ILCs in the initiation and progression in tissue inflammation and delineate a novel innate immune cell-mediated pathogenic mechanism through which redox regulation may determine the direction of immune responses in joints.


Assuntos
Interleucina-1beta/imunologia , Linfócitos/imunologia , NADPH Oxidase 2/deficiência , Espécies Reativas de Oxigênio/imunologia , Tarso Animal/imunologia , Animais , Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-1beta/genética , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2/genética , NADPH Oxidase 2/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Oxirredução/efeitos dos fármacos , Fagócitos/efeitos dos fármacos , Fagócitos/imunologia , Fagócitos/patologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Soro/imunologia , Transdução de Sinais , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Tarso Animal/efeitos dos fármacos , Tarso Animal/patologia
16.
J Autoimmun ; 105: 102307, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31351783

RESUMO

NK cells are thought to develop primarily in the bone marrow during adult life. However, increasing evidence shows that NK cell developmental intermediates can be found in different peripheral tissues with unique characteristics. Here, we identified a unique NK cell subset with the CD49a-CD49b- phenotype in the spleen. These cells displayed an immature phenotype and weak abilities in cytotoxicity and cytokine production. Adoptive transfer experiments revealed that they could develop into mature conventional NK (cNK) cells. Transcriptome analysis further confirmed their immature features. Parabiosis experiments revealed that these cells maintained tissue-resident properties in the spleen. Moreover, T-bet deficiency intrinsically impaired the ability of these cells to develop into mature cNK cells. Thus, our study identified a spleen-resident immature NK cell subset that could undergo extramedullary maturation in a T-bet dependent manner.


Assuntos
Células Matadoras Naturais/imunologia , Baço/imunologia , Proteínas com Domínio T/imunologia , Animais , Células Cultivadas , Citocinas/imunologia , Integrina alfa1/imunologia , Fígado/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Parabiose/métodos , Transcriptoma/imunologia
17.
Fish Shellfish Immunol ; 93: 28-38, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302288

RESUMO

Eomesodermin (Eomes) is a member of T-box transcription factor family and plays an important role in the regulation of a wide variety of developmental processes and immune response in animals. Here we report cloning and characterization of the full-length cDNA of Atlantic cod Eomes (GmEomes), which possesses a TBOX_3 domain similar to its counterpart in mammals. The regulated expression was observed in head kidney and spleen in response to live Vibrio anguillarum infection in vivo, and spleen leukocytes in vitro after PMA and poly I:C stimulation. Furthermore, we determined a 694 bp sequence, upstream of the transcriptional start site (TSS), to contain a number of sequence motifs that matched known transcription factor-binding sites. Activities of the presumptive regulatory gene were assessed by transfecting different 5'-deletion constructs in CHSE-214 cells. The results showed that the basal promoters and positive transcriptional regulator activities of GmEomes were dependent by sequences located from -694 to -376 bp upstream of TSS. Furthermore, we found that some Eomes binding sites were present in the 5'-flanking regions of the cod IFNγ gene predicted by bioinformatics. However, Co-transfection of eomesodermin overexpression plasmids with INFγ reporter vector into CHSE-214 cells determined that Atlantic cod eomesodermin played a minor role in activation of the INFγ promoter.


Assuntos
Doenças dos Peixes/imunologia , Gadus morhua/genética , Gadus morhua/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Filogenia , Poli I-C/farmacologia , Alinhamento de Sequência/veterinária , Proteínas com Domínio T/química , Acetato de Tetradecanoilforbol/farmacologia , Vibrio/fisiologia , Vibrioses/imunologia , Vibrioses/veterinária
18.
Int Immunopharmacol ; 74: 105675, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177017

RESUMO

Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder. Autoreactive T cells play a very significant role in the pathogenesis of RA. However, the exact mechanisms of disease severity and pathogenesis are poorly understood. We attempted to correlate T-helper cell activities with sexes of newly diagnosed patients with RA. The patients were divided based on their sex and disease severity. Examination of the expression of various factors using quantitative real-time PCR and FACS analysis of peripheral blood mononuclear cells revealed that T-bet, ROR-γt, Foxp3, and the level of cytokines associated with Th1 cells were almost identical among male and female patients with RA. Interestingly, there was a high correlation between Th17 expression and disease severity in female patients with RA. In general, there was no significant correlation between Th1 cell population and the disease severity in newly diagnosed patients with RA. In contrast, the frequency of both Th17 and Treg cells was higher in patients with more severe disease. The results suggested that, in patients with RA, the T-helper cell balance within peripheral blood was skewed towards the Th17 and Treg phenotypes. Besides Th17- and Treg-associated cytokines, elevated expression of IL-27/IL-23 cytokines might also be responsible for increased disease severity in female patients with RA.


Assuntos
Artrite Reumatoide/imunologia , Adulto , Citocinas/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Caracteres Sexuais , Proteínas com Domínio T/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia
19.
J Immunol ; 203(4): 1044-1054, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31227580

RESUMO

Virus infection triggers large-scale changes in the phenotype and function of naive CD8+ T cells, resulting in the generation of effector and memory T cells that are then critical for immune clearance. The T-BOX family of transcription factors (TFs) are known to play a key role in T cell differentiation, with mice deficient for the TF T-BET (encoded by Tbx21) unable to generate optimal virus-specific effector responses. Although the importance of T-BET in directing optimal virus-specific T cell responses is accepted, the precise timing and molecular mechanism of action remains unclear. Using a mouse model of influenza A virus infection, we demonstrate that although T-BET is not required for early CD8+ T cell activation and cellular division, it is essential for early acquisition of virus-specific CD8+ T cell function and sustained differentiation and expansion. Whole transcriptome analysis at this early time point showed that Tbx21 deficiency resulted in global dysregulation in early programming events with inappropriate lineage-specific signatures apparent with alterations in the potential TF binding landscape. Assessment of histone posttranslational modifications within the Ifng locus demonstrated that Tbx21 -/- CD8+ T cells were unable to activate "poised" enhancer elements compared with wild-type CD8+ T cells, correlating with diminished Ifng transcription. In all, these data support a model whereby T-BET serves to promote appropriate chromatin remodeling at specific gene loci that underpins appropriate CD8+ T cell lineage-specific commitment and differentiation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Infecções por Orthomyxoviridae/imunologia , Proteínas com Domínio T/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Vírus da Influenza A/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transcrição Genética/imunologia
20.
Cell Immunol ; 341: 103928, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31178059

RESUMO

Asthma is a chronic disease with impacts on public health. It affects the airways causing pulmonary inflammation mediated by CD4 T cells type Th2, eosinophilia, mucus hypersecretion, and elevated IgE. The unbalance between cytokines and transcription factors is an important feature in asthma. Probiotics has gaining highlight as a therapy for chronic diseases. Thus, we investigate the Lactobacillus bulgaricus (Lb) effect in murine allergic asthma. BALB/c-mice were sensitized to ovalbumin (OA) on days 0 and 7 and were challenged from day 14-28 with OA. Mice received Lb seven days prior to sensitization and it was kept until day 28. The Lb attenuated the eosinophils infiltration, mucus and collagen secretion, IgE production, pro-inflammatory cytokines, TLR4 expression, GATA3, STAT6 and RORγt in lung. Otherwise, Lb increased the anti-inflammatory cytokines, the T-bet and foxp3. Finally, Lb attenuated the allergic asthma-induced inflammation and airway remodeling by interfering on Th1/Th2 cytokines and STAT6/T-bet transcription factors.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/prevenção & controle , Lactobacillus delbrueckii/imunologia , Pneumonia/prevenção & controle , Probióticos/farmacologia , Fator de Transcrição STAT6/imunologia , Proteínas com Domínio T/imunologia , Remodelação das Vias Aéreas/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/microbiologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/patologia , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Regulação da Expressão Gênica , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Ovalbumina/administração & dosagem , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/microbiologia , Fator de Transcrição STAT6/genética , Transdução de Sinais , Proteínas com Domínio T/genética , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/patologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/patologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia
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