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1.
Adv Exp Med Biol ; 1224: 35-51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32036603

RESUMO

CD4+ T helper (TH) cells are key regulators in the tumour immune microenvironment (TIME), mediating the adaptive immunological response towards cancer, mainly through the activation of cytotoxic CD8+ T cells. After antigen recognition and proper co-stimulation, naïve TH cells are activated, undergo clonal expansion, and release cytokines that will define the differentiation of a specific effector TH cell subtype. These different subtypes have different functions, which can mediate both anti- and pro-tumour immunological responses. Here, we present the dual role of TH cells restraining or promoting the tumour, the factors controlling their homing and differentiation in the TIME, their influence on immunotherapy, and their use as prognostic indicators.


Assuntos
Neoplasias/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Microambiente Tumoral/imunologia , Animais , Citocinas/metabolismo , Humanos , Linfócitos T Citotóxicos/imunologia
2.
Immunity ; 52(1): 183-199.e9, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31924475

RESUMO

Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional profiles of 131,224 single cells from peripheral and intra-tumoral immune populations from patients with HPV- and HPV+ HNSCC and healthy donors. Immune cells within tumors of HPV- and HPV+ HNSCC displayed a spectrum of transcriptional signatures, with helper CD4+ T cells and B cells being relatively divergent and CD8+ T cells and CD4+ regulatory T cells being relatively similar. Transcriptional results were contextualized through multispectral immunofluorescence analyses and evaluating putative cell-cell communication based on spatial proximity. These analyses defined a gene expression signature associated with CD4+ T follicular helper cells that is associated with longer progression-free survival in HNSCC patients. The datasets and analytical approaches herein provide a resource for the further study of the impact of immune cells on viral- and carcinogen-induced cancers.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Alphapapillomavirus/imunologia , Diferenciação Celular/imunologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imunoterapia , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
3.
Scand J Immunol ; 91(1): e12813, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31386235

RESUMO

BACKGROUND: Sepsis is a life-threatening disease that is an immune disorder response that causes multiple organ dysfunction. In this study, we investigated the dynamic changes in mRNA expression of HLA-DRA gene and the specific transcription factor of helper T cell subsets to explore long-term immunophenotyping and its relationship with prognosis. METHODS: Seventy-eight sepsis patients and twelve healthy controls were recruited in this study. Blood samples were collected at eight-time points during their septic course and were assayed for the gene expression of HLA-DRA and T helper cell subset-specific transcription factors (T-bet: Th1, GATA3: Th2, Foxp3: Treg, RORC: Th17). RESULTS: The levels of HLA-DRA in survivors gradually increased but were maintained at lower levels in non-survivors. The specific transcription factor of Th1 and Th2 cells, T-bet and GATA-3 were significantly lower in sepsis patients than in normal controls, and the non-survivors showed significantly lower levels than the survivors (P < .05). RORC and FOXP3, the specific transcription factor of Treg and Th17 were significantly higher in survivors than in non-survivors and normal controls (P < .05). T-bet and GATA-3 had a linear correlation with HLA-DRA expression (P < .01). CONCLUSIONS: The dynamic changes in HLA-DRA expression in peripheral blood could accurately reflect the immune status of sepsis patients, and the reduction in HLA-DRA may be an important reason for abnormal T cell differentiation. The sustained low levels of the Th cell subsets (Th1 and Th2) suggest the suppression of adaptive immunity, and this persistent immunosuppression may be the leading cause of death in septic patients.


Assuntos
Regulação da Expressão Gênica , Cadeias alfa de HLA-DR/genética , Sepse/etiologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Adulto , Idoso , Biomarcadores , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Sepse/diagnóstico , Sepse/mortalidade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Cell Mol Life Sci ; 77(2): 289-303, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31432236

RESUMO

CD4 T-helper (Th) cells secret a variety of inflammatory cytokines and play critical roles in host defense against invading foreign pathogens. On the other hand, uncontrolled inflammatory responses mediated by Th cells may result in tissue damage and inflammatory disorders including autoimmune and allergic diseases. Thus, the induction of anti-inflammatory cytokine expression becomes an important "brake" to repress and/or terminate aberrant and/or unnecessary immune responses. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines to limit inflammatory Th cells and immunopathology and to maintain tissue homeostasis. Many studies have indicated that Th cells can be a major source of IL-10 under specific conditions both in mouse and human and that extracellular signals and cell intrinsic molecular switches are required to turn on and off Il10 expression in different Th cells. In this review, we will highlight the recent findings that have enhanced our understanding on the mechanisms of IL-10 induction in distinct Th-cell subsets, including Th1, Th2, and Th17 cells, as well as the importance of these IL-10-producing anti-inflammatory Th cells in immunity and inflammation.


Assuntos
Anti-Inflamatórios/imunologia , Diferenciação Celular/imunologia , Inflamação/imunologia , Interleucina-10/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Humanos
5.
Immunity ; 52(1): 83-95.e4, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31882362

RESUMO

Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). However, these cells are not derived from the ILC common progenitor, which generates other ILC subsets and is defined by the expression of the transcription factor PLZF. Here, we examined transcription factor(s) determining the fate of LTi progenitors versus non-LTi ILC progenitors. Conditional deletion of Gata3 resulted in the loss of PLZF+ non-LTi progenitors but not the LTi progenitors that expressed the transcription factor RORγt. Consistently, PLZF+ non-LTi progenitors expressed high amounts of GATA3, whereas GATA3 expression was low in RORγt+ LTi progenitors. The generation of both progenitors required the transcriptional regulator Id2, which defines the common helper-like innate lymphoid progenitor (ChILP), but not cytokine signaling. Nevertheless, low GATA3 expression was necessary for the generation of functionally mature LTi cells. Thus, differential expression of GATA3 determines the fates and functions of distinct ILC progenitors.


Assuntos
Fator de Transcrição GATA3/biossíntese , Células-Tronco/citologia , Subpopulações de Linfócitos T/citologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Linhagem da Célula/imunologia , Células Cultivadas , Fator de Transcrição GATA3/genética , Proteína 2 Inibidora de Diferenciação/metabolismo , Subunidade gama Comum de Receptores de Interleucina/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese , Receptor de Morte Celular Programada 1/biossíntese , Proteína com Dedos de Zinco da Leucemia Promielocítica/biossíntese , Células-Tronco/imunologia , Subpopulações de Linfócitos T/imunologia
6.
Immunity ; 51(5): 826-839.e5, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31732165

RESUMO

T follicular helper (Tfh) cells provide essential help to B cells in germinal center (GC) reactions. Bcl6 is the obligatory lineage transcription factor in Tfh cells. Here, we examined the molecular pathways that induce Bcl6 gene expression and underscore Bcl6-dependent function during Tfh cell commitment. Integration of genome-wide Bcl6 occupancy in Tfh cells and differential gene expression analyses suggested an important role for the transcription factor Tox2 in Tfh cell differentiation. Ectopic expression of Tox2 was sufficient to drive Bcl6 expression and Tfh development. In genome-wide ChIP-seq analyses, Tox2-bound loci associated with Tfh cell differentiation and function, including Bcl6. Tox2 binding was associated with increased chromatin accessibility at these sites, as measured by ATAC-seq. Tox2-/- mice exhibited defective Tfh differentiation, and inhibition of both Tox2 and the related transcription factor Tox abolished Tfh differentiation. Thus, a Tox2-Bcl6 axis establishes a transcriptional feed-forward loop that promotes the Tfh program.


Assuntos
Montagem e Desmontagem da Cromatina , Cromatina/genética , Cromatina/metabolismo , Proteínas de Homeodomínio/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Diferenciação Celular/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/metabolismo
7.
Eur J Histochem ; 63(4)2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31631646

RESUMO

The peripheral nervous system communicates specifically with the immune system via local interactions. These interactions include the "hardwiring" of sympathetic/parasympathetic (efferent) and sensory nerves (afferent) to primary (e.g., thymus and bone marrow) and secondary (e.g., lymph node, spleen, and gut-associated lymphoid tissue) lymphoid tissue/organs. To gain a better understanding of this bidirectional interaction/crosstalk between the two systems, we have investigated the distribution of nerve fibres and PNS-immune cell associations in situ in the mouse lymph node by using immunofluorescent staining and confocal microscopy/ three-dimensional reconstruction. Our results demonstrate i) the presence of extensive nerve fibres in all compartments (including B cell follicles) in the mouse lymph node; ii) close contacts/associations of nerve fibres with blood vessels (including high endothelial venules) and lymphatic vessels/sinuses; iii) close contacts/associations of nerve fibres with various subsets of dendritic cells (e.g., B220+CD11c+, CD4+CD11c+, CD8a+CD11c+, and Mac1+CD11c+), Mac1+ macrophages, and B/T lymphocytes. Our novel findings concerning the innervation and nerve-immune cell interactions inside the mouse lymph node should greatly facilitate our understanding of the effects that the peripheral nervous system has on cellular- and humoral-mediated immune responses or vice versa in health and disease.


Assuntos
Linfonodos/imunologia , Linfonodos/inervação , Animais , Anticorpos Monoclonais/imunologia , Cricetulus , Células Dendríticas/imunologia , Imunofluorescência , Cabras , Masculino , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia de Fluorescência , Fibras Nervosas/metabolismo , Coelhos , Ratos , Linfócitos T Auxiliares-Indutores/imunologia
8.
Toxicol Lett ; 316: 147-153, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520700

RESUMO

Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM2.5 and cold stress contribute to the development of asthma. However, the combined effects of these two risking factors are unknown. In this study, we investigated the combined effects of PM2.5 exposure and cold stress (PMCS) on asthma, as well as the underlying mechanisms by using a murine model. After different exposures, the immune-pathological changes and redox states in groups were evaluated. Besides, the balance of TH1/TH2 cells and the acetylation levels of H3K9 and H3K14 in IL-4 gene promotor were detected. Our results showed that, compared with other exposures, PMCS led to an increased inflammation and redox levels in mice. It also significantly increased the percentage of TH2 T cells, which was correlated with hyperacetylation of H3K9 and H3K14 in IL-4 gene promoter in CD4+T cells. Furthermore, a significantly increased P300 and decreased HDAC1 were detected in CD4 + T cells in PMCS group. In conclusion, our findings demonstrated that PMCS exacerbated asthma in mice by increasing H3K9 and H3K14 acetylation in IL-4 gene promoter in CD4 + T cells, and P300 and HDAC1 might contribute to their combined effects.


Assuntos
Asma/induzido quimicamente , Temperatura Baixa/efeitos adversos , Histonas/metabolismo , Interleucina-4/metabolismo , Pulmão/efeitos dos fármacos , Material Particulado/toxicidade , Regiões Promotoras Genéticas , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Acetilação , Animais , Asma/genética , Asma/imunologia , Asma/metabolismo , Modelos Animais de Doenças , Proteína p300 Associada a E1A/metabolismo , Histona Desacetilase 1/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Ovalbumina , Tamanho da Partícula , Processamento de Proteína Pós-Traducional , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
9.
Nat Commun ; 10(1): 4415, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562329

RESUMO

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores CXCR5/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos B/metabolismo , Antígenos CD40/genética , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/genética , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Tolerância Imunológica/genética , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Fator de Transcrição STAT5/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
10.
Infect Immun ; 87(12)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31548315

RESUMO

Nontypeable Haemophilus influenzae (NTHi) is a major pathogen causing acute otitis media (AOM). The pathology of AOM increases during long-term infection in the middle ear (ME), but the host cellular immune response to bacterial infection in this inflamed environment is poorly understood. Using the Junbo mouse, a characterized NTHi infection model, we analyzed the cellular response to NTHi infection in the Junbo mouse middle ear fluid (MEF). NTHi infection increased the total cell number and significantly decreased the proportion of live cells in the MEF at day 1, and this further decreased gradually on each day up to day 7. Flow cytometry analysis showed that neutrophils were the dominant immune cell population in the MEF and that NTHi infection significantly increased their proportion whereas it decreased the monocyte, macrophage, and dendritic cell proportions. Neutrophil and macrophage numbers increased in blood and spleen after NTHi infection. The T-cell population was dominated by T-helper (Th) cells in noninoculated MEF, and the effector Th (CD44+) cell population increased at day 2 of NTHi infection with an increase in IL-12p40 levels. Sustained NTHi infection up to 3 days increased the transforming growth factor ß levels, decreasing the effector cell population and increasing the T-regulatory (T-reg) cell population. In the preinflamed ME environment of the Junbo mouse, neutrophils are the first responder to NTHi infection followed by T-reg immune suppressive cells. These data indicate that sustained NTHi infection in the ME induces the immune suppressive response by inducing the T-reg cell population and reducing immune cell infiltration, thus promoting longer-term infection.


Assuntos
Orelha Média/patologia , Infecções por Haemophilus/patologia , Haemophilus influenzae/imunologia , Neutrófilos/imunologia , Otite Média com Derrame/patologia , Linfócitos T Reguladores/imunologia , Animais , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Orelha Média/microbiologia , Infecções por Haemophilus/microbiologia , Subunidade p40 da Interleucina-12/metabolismo , Macrófagos/imunologia , Camundongos , Otite Média com Derrame/microbiologia , Linfócitos T Auxiliares-Indutores/imunologia , Fator de Crescimento Transformador beta1/metabolismo
11.
DNA Cell Biol ; 38(10): 1040-1047, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31414895

RESUMO

The helper T cell 9 (Thelper-9, Th9), as a functional subgroup of CD4+T cells, was first discovered in 2008. Th9 cells expressed transcription factor PU.1 and cytokine interleukin-9 (IL-9) characteristically. Recent researches have shown that the differentiation of Th9 cells was coregulated by cytokine transforming growth factor ß, IL-4, and various transcription factors. Th9 cells, as a new player, played an important role in various immune-related diseases, including tumors, inflammatory diseases, parasite infection, and other diseases. In this article, we summarize the related research progress and discuss the possible prospect.


Assuntos
Interleucina-9/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Neoplasias/imunologia , Proteínas Proto-Oncogênicas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transativadores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Diferenciação Celular , Fator de Transcrição GATA3/deficiência , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Regulação da Expressão Gênica , Humanos , Inflamação , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-9/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Knockout , Neoplasias/genética , Neoplasias/patologia , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/patologia , Transativadores/genética , Fator de Crescimento Transformador beta/genética
12.
Mol Immunol ; 114: 243-250, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31394381

RESUMO

Age-related macular degeneration (AMD) is the most common cause of vision loss in the aged population. Aging and inflammation are thought to promote AMD pathogenesis in people with genetic predisposition. Follicular helper T (Tfh) cells play critical roles in inflammatory responses. Here, we investigated circulating Tfh cells in AMD patients. Circulating Tfh cells were defined as CXCR5+ CD4 T cells. Data showed that patients with the wet-type AMD presented significantly higher levels of Tfh cells than non-AMD controls. Interestingly, the Tfh cells from dry and wet AMD patients also presented significantly higher ICOS and PD-1 expression, together with higher IL-17 and IL-21 expression directly ex vivo and following PMA/ionomycin stimulation. The expression of IFNg and IL-10, on the other hand, was not different between Tfh cells from AMD patients and their counterparts in non-AMD controls. Functional analysis revealed that Tfh cells from AMD patients were better at inducing the production of IgG and IgA, and this effect was in an IL-21-dependent manner. Together, we demonstrated that the circulating Tfh cell responses were dysregulated in AMD patients.


Assuntos
Interleucinas/imunologia , Degeneração Macular/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Linfócitos T CD4-Positivos/imunologia , Técnicas de Cocultura/métodos , Citocinas/imunologia , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Interferon gama/imunologia , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade
13.
Nat Commun ; 10(1): 3859, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455769

RESUMO

Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses.


Assuntos
Switching de Imunoglobulina/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Infecção por Zika virus/imunologia , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos , Camundongos Knockout , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Células Vero , Infecção por Zika virus/virologia
14.
Immunity ; 51(3): 465-478.e6, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31422869

RESUMO

The generation of high-affinity neutralizing antibodies, the objective of most vaccine strategies, occurs in B cells within germinal centers (GCs) and requires rate-limiting "help" from follicular helper CD4+ T (Tfh) cells. Although Tfh differentiation is an attribute of MHC II-restricted CD4+ T cells, the transcription factors driving Tfh differentiation, notably Bcl6, are not restricted to CD4+ T cells. Here, we identified a requirement for the CD4+-specific transcription factor Thpok during Tfh cell differentiation, GC formation, and antibody maturation. Thpok promoted Bcl6 expression and bound to a Thpok-responsive region in the first intron of Bcl6. Thpok also promoted the expression of Bcl6-independent genes, including the transcription factor Maf, which cooperated with Bcl6 to mediate the effect of Thpok on Tfh cell differentiation. Our findings identify a transcriptional program that links the CD4+ lineage with Tfh differentiation, a limiting factor for efficient B cell responses, and suggest avenues to optimize vaccine generation.


Assuntos
Diferenciação Celular/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Proteínas Proto-Oncogênicas c-maf/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/imunologia , Transcrição Genética/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Centro Germinativo/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL
15.
Mol Immunol ; 114: 323-329, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31442916

RESUMO

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that occurs in the gastrointestinal tract, characterized by an upregulation in autoantibody production and antimicrobial antibody production. The interaction between follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) is critical to the induction and regulation of antibody production. In this study, we investigated the characteristics of Tfr cells in UC patients. We gated circulating Tfr cells as CD4+CXCR5+CD25+CD127- T cells, of which approximately 73% on average were Foxp3+. The circulating Tfh (CD4+CXCR5+CD25-) cells from control subjects and UC patients presented a comparable capacity to induce IgM production from naive B cells and to mediate class switching to IgG. Tfr cells significantly reduced Tfh-mediated B cell help in both healthy controls and UC patients in a concentration-dependent manner. However, the suppression capacity of Tfr cells was significantly lower in UC patients than in healthy controls. Subsequently, we found that the frequency of CTLA-4-expressing cells was only slightly lower in UC patients, but the MFI of CTLA-4, however, was markedly lower in UC patients. CTLA-4 blockade nearly abrogated Tfr-mediated suppression of IgM, and significantly reduced Tfr-mediated suppression of IgG. Moreover, CTLA-4 blockade removed the relative advantage of Tfr suppression capacity in healthy controls compared to UC patients. Overall, this study demonstrated that CTLA-4 was required for Tfr-mediated suppression of B cell help, but was expressed at lower levels in UC patients.


Assuntos
Antígeno CTLA-4/imunologia , Colite Ulcerativa/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Imunoglobulina M/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR5/imunologia , Linfócitos T Auxiliares-Indutores/imunologia
16.
Immunity ; 51(2): 337-350.e7, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31375460

RESUMO

Class-switch recombination (CSR) is a DNA recombination process that replaces the immunoglobulin (Ig) constant region for the isotype that can best protect against the pathogen. Dysregulation of CSR can cause self-reactive BCRs and B cell lymphomas; understanding the timing and location of CSR is therefore important. Although CSR commences upon T cell priming, it is generally considered a hallmark of germinal centers (GCs). Here, we have used multiple approaches to show that CSR is triggered prior to differentiation into GC B cells or plasmablasts and is greatly diminished in GCs. Despite finding a small percentage of GC B cells expressing germline transcripts, phylogenetic trees of GC BCRs from secondary lymphoid organs revealed that the vast majority of CSR events occurred prior to the onset of somatic hypermutation. As such, we have demonstrated the existence of IgM-dominated GCs, which are unlikely to occur under the assumption of ongoing switching.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Switching de Imunoglobulina , Plasmócitos/imunologia , Linfoma Plasmablástico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Filogenia , Receptores de Antígenos de Linfócitos B/metabolismo
17.
Mol Immunol ; 114: 162-170, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31352232

RESUMO

Clinically, most patients with primary nephrotic syndrome (PNS) have low serum IgG levels, which is an important factor in infection and in PNS relapse.To some extent, the mechanisms involved remain largely unknown. Here, we aimed to investigate the pathogenesis of the decreased IgG levels in PNS. Peripheral blood was collected from patients with PNS and closely age- and sex-matched healthy individuals. The frequency, phenotype and molecular function of different circulating B cell and T follicular helper cell (TFH) subsets were examined by flow cytometry. The function of the CD40/CD40 L interaction in immunoglobulin class-switch recombination (CSR) was evaluated by assessing the induction of activation-induced deaminase (AID) expression with CD40 L stimulation. We revealed an increase in the levels of circulating total plasmablasts, plasma cells and mature-naive B cells and a decrease in the levels of germinal centre-like B cells and CD19+IgG+ B cells in PNS. In addition, although the expression of CD86 on the surface of B cells and the expression of the inducible costimulator (ICOS) on the surface of TFH cells both were increased, the expression of CD40 L on the surface of TFH cells was decreased. Moreover, upon stimulation with CD40 L in vitro, the mRNA expression of AID in peripheral blood mononuclear cells (PBMCs) was decreased in patients with PNS compared with that in healthy controls. Our results indicate that the immunoglobulin CSR of B cells was partly dysfunctional and provide insights into the potential involvement of impaired TFH cell-dependent B cell responses in the pathogenesis of low IgG levels through downregulating CD40 L expression on TFH cells in PNS.


Assuntos
Linfócitos B/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Síndrome Nefrótica/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Autoanticorpos/imunologia , Ligante de CD40/imunologia , Criança , Pré-Escolar , Feminino , Centro Germinativo/imunologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Lactente , Interleucinas/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Síndrome Nefrótica/sangue , Plasmócitos/imunologia
18.
J Neuroinflammation ; 16(1): 149, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324254

RESUMO

BACKGROUND: Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied. METHODS: We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined. RESULTS: Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4+ T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3+ regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ+, IL-17+, and GM-CSF+ CD4+ T cells, while it induced CD4+ Foxp3+ regulatory T cells in splenocytes by flow cytometry. CONCLUSIONS: Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Quinazolinonas/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Animais , Inibidores Enzimáticos/farmacologia , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas de Ligação a RNA/antagonistas & inibidores , Linfócitos T Auxiliares-Indutores/imunologia
19.
Immunohorizons ; 3(3): 88-93, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31342012

RESUMO

The CD1d-binding glycolipid α-galactosylceramide (α-GC) is a potent adjuvant that activates NKT cells and in turn enhances T-dependent humoral immunity. Very little is known about how NKT cells and the NKT follicular helper (NKTfh) subset influence the immune response to T-independent polysaccharides. In this study, we used a Cre-Lox approach to generate mice devoid of the Bcl6 master transcription factor in CD4 lineage cells and thus devoid of NKTfh cells but not total NKT cells. It was observed that α-GC-driven IgG1 class switch against a polysaccharide Ag was dependent on the NKTfh subset. However, α-GC was unable to stimulate a polysaccharide-specific Ab recall response. It was observed that NKT-derived IL-21 was able to exert limited influence on the IgG1 response and was therefore likely to work in concert with other factors. This work shows that α-GC-driven NKTfh cells can direct polysaccharide-specific B cell responses by promoting IgG1 class switch but do not provide signals needed for generation of polysaccharide-specific B cell memory.


Assuntos
Switching de Imunoglobulina/imunologia , Imunoglobulina G/imunologia , Memória Imunológica , Células T Matadoras Naturais/imunologia , Polissacarídeos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular , Feminino , Galactosilceramidas/imunologia , Imunização , Switching de Imunoglobulina/genética , Imunoglobulina G/genética , Ativação Linfocitária , Masculino , Camundongos , Camundongos Transgênicos , Células T Matadoras Naturais/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
20.
Nat Med ; 25(8): 1290-1300, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332391

RESUMO

Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here, we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing-remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte-macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing-remitting multiple sclerosis. In independent validation cohorts, we confirmed that this cell population is increased in patients with MS compared with other inflammatory and non-inflammatory conditions. Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Esclerose Múltipla/imunologia , Receptores CXCR4/biossíntese , Linfócitos T Auxiliares-Indutores/imunologia , Algoritmos , Citocinas/biossíntese , Humanos , Memória Imunológica , Esclerose Múltipla/líquido cefalorraquidiano
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