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1.
Immunity ; 56(10): 2358-2372.e5, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37699392

RESUMO

Lung-resident memory B cells (lung-BRMs) differentiate into plasma cells after reinfection, providing enhanced pulmonary protection. Here, we investigated the determinants of lung-BRM differentiation upon influenza infection. Kinetic analyses revealed that influenza nucleoprotein (NP)-specific BRMs preferentially differentiated early after infection and required T follicular helper (Tfh) cell help. BRM differentiation temporally coincided with transient interferon (IFN)-γ production by Tfh cells. Depletion of IFN-γ in Tfh cells prevented lung-BRM differentiation and impaired protection against heterosubtypic infection. IFN-γ was required for expression of the transcription factor T-bet by germinal center (GC) B cells, which promoted differentiation of a CXCR3+ GC B cell subset that were precursors of lung-BRMs and CXCR3+ memory B cells in the mediastinal lymph node. Absence of IFN-γ signaling or T-bet in GC B cells prevented CXCR3+ pre-memory precursor development and hampered CXCR3+ memory B cell differentiation and subsequent lung-BRM responses. Thus, Tfh-cell-derived IFN-γ is critical for lung-BRM development and pulmonary immunity, with implications for vaccination strategies targeting BRMs.


Assuntos
Influenza Humana , Linfócitos T Auxiliares-Indutores , Humanos , Interferon gama/metabolismo , Células B de Memória , Células T Auxiliares Foliculares/metabolismo , Centro Germinativo , Diferenciação Celular , Receptores CXCR3/metabolismo
2.
Nat Immunol ; 18(11): 1249-1260, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28892471

RESUMO

Interleukin 2 (IL-2) promotes Foxp3+ regulatory T (Treg) cell responses, but inhibits T follicular helper (TFH) cell development. However, it is not clear how IL-2 affects T follicular regulatory (TFR) cells, a cell type with properties of both Treg and TFH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented TFR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some Treg cells downregulated CD25, upregulated Bcl-6 and differentiated into TFR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional Treg cells, IL-2 inhibits TFR cell responses.


Assuntos
Interleucina-2/farmacologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Movimento Celular/genética , Movimento Celular/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica/métodos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Orthomyxoviridae/fisiologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
3.
Immunity ; 50(1): 225-240.e4, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30635238

RESUMO

Infants have a higher risk of developing allergic asthma than adults. However, the underlying mechanism remains unknown. We show here that sensitization of mice with house-dust mites (HDMs) in the presence of low-dose lipopolysaccharide (LPS) prevented T helper 2 (Th2) cell allergic responses in adult, but not infant, mice. Mechanistically, adult CD11b+ migratory dendritic cells (mDCs) upregulated the transcription factor T-bet in response to tumor necrosis factor-α (TNF-α), which was rapidly induced after HDM + LPS sensitization. Consequently, adult CD11b+ mDCs produced interleukin-12 (IL-12), which prevented Th2 cell development by promoting T-bet upregulation in responding T cells. Conversely, infants failed to induce TNF-α after HDM + LPS sensitization. Therefore, CD11b+ mDCs failed to upregulate T-bet and did not secrete IL-12 and Th2 cell responses normally developed in infant mice. Thus, the availability of TNF-α dictates the ability of CD11b+ mDCs to suppress allergic Th2-cell responses upon dose-dependent endotoxin sensitization and is a key mediator governing susceptibility to allergic airway inflammation in infant mice.


Assuntos
Células Dendríticas/fisiologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Antígenos de Dermatophagoides , Diferenciação Celular , Humanos , Imunização , Lactente , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pyroglyphidae/imunologia , Proteínas com Domínio T/metabolismo
4.
Immunity ; 50(5): 1172-1187.e7, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31076359

RESUMO

Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses.


Assuntos
Linfócitos B/imunologia , Interferon gama/imunologia , Receptores de Interferon/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Células Produtoras de Anticorpos/imunologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Células Cultivadas , Cromatina/metabolismo , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nematospiroides dubius/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/biossíntese , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia , Proteínas com Domínio T/genética , Receptor de Interferon gama
5.
Immunity ; 47(2): 251-267.e7, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28813658

RESUMO

Despite considerable research connecting cellular metabolism with differentiation decisions, the underlying mechanisms that translate metabolite-sensitive activities into unique gene programs are still unclear. We found that aspects of the interleukin-2 (IL-2)-sensitive effector gene program in CD4+ and CD8+ T cells in type 1 conditions (Th1) were regulated by glutamine and alpha-ketoglutarate (αKG)-induced events, in part through changes in DNA and histone methylation states. We further identified a mechanism by which IL-2- and αKG-sensitive metabolic changes regulated the association of CCCTC-binding factor (CTCF) with select genomic sites. αKG-sensitive CTCF sites were often associated with loci containing IL-2- and αKG-sensitive genome organization patterns and gene expression in T cells. IL-2- and αKG-sensitive CTCF sites in T cells were also associated with genes from developmental pathways that had αKG-sensitive expression in embryonic stem cells. The data collectively support a mechanism wherein CTCF serves to translate αKG-sensitive metabolic changes into context-dependent differentiation gene programs.


Assuntos
Diferenciação Celular , Interleucina-2/metabolismo , Ácidos Cetoglutáricos/metabolismo , Proteínas Repressoras/metabolismo , Células Th1/imunologia , Animais , Fator de Ligação a CCCTC , Diferenciação Celular/genética , Células Cultivadas , Microambiente Celular , Metilação de DNA , Feminino , Regulação da Expressão Gênica , Glutamina/metabolismo , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Repressoras/genética
6.
Immunity ; 44(2): 259-73, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26825674

RESUMO

Exposure to environmental antigens, such as house dust mite (HDM), often leads to T helper 2 (Th2) cell-driven allergic responses. However, the mechanisms underlying the development of these responses are incompletely understood. We found that the initial exposure to HDM did not lead to Th2 cell development but instead promoted the formation of interleukin-4 (IL-4)-committed T follicular helper (Tfh) cells. Following challenge exposure to HDM, Tfh cells differentiated into IL-4 and IL-13 double-producing Th2 cells that accumulated in the lung and recruited eosinophils. B cells were required to expand IL-4-committed Tfh cells during the sensitization phase, but did not directly contribute to disease. Impairment of Tfh cell responses during the sensitization phase or Tfh cell depletion prevented Th2 cell-mediated responses following challenge. Thus, our data demonstrate that Tfh cells are precursors of HDM-specific Th2 cells and reveal an unexpected role of B cells and Tfh cells in the pathogenesis of allergic asthma.


Assuntos
Asma/imunologia , Linfócitos B/imunologia , Hipersensibilidade/imunologia , Células Th2/imunologia , Animais , Antígenos de Dermatophagoides/administração & dosagem , Antígenos de Dermatophagoides/imunologia , Asma/etiologia , Diferenciação Celular , Células Cultivadas , Humanos , Hipersensibilidade/complicações , Imunidade , Inalação , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Depleção Linfocítica , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pyroglyphidae
7.
Immunity ; 45(4): 831-846, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27760339

RESUMO

T follicular helper (Tfh) cells are a CD4+ T cell subset critical for long-lived humoral immunity. We hypothesized that integrins play a decisive role in Tfh cell biology. Here we show that Tfh cells expressed a highly active form of leukocyte function-associated antigen-1 (LFA-1) that was required for their survival within the germinal center niche. In addition, LFA-1 promoted expression of Bcl-6, a transcriptional repressor critical for Tfh cell differentiation, and inhibition of LFA-1 abolished Tfh cell generation and prevented protective humoral immunity to intestinal helminth infection. Furthermore, we demonstrated that expression of Talin-1, an adaptor protein that regulates LFA-1 affinity, dictated Tfh versus Th2 effector cell differentiation. Collectively, our results define unique functions for LFA-1 in the Tfh cell effector program and suggest that integrin activity is important in lineage decision-making events in the adaptive immune system.


Assuntos
Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Células Cultivadas , Centro Germinativo/imunologia , Humanos , Imunidade Humoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/imunologia
8.
Nat Immunol ; 13(7): 681-90, 2012 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-22634865

RESUMO

Although cognate encounters between antigen-bearing dendritic cells (DCs) that express the chemokine receptor CCR7 and CCR7(+) naive T cells take place in the T cell zone of lymph nodes, it is unknown whether the colocalization of DCs and T cells in the T cell area is required for the generation of effector cells. Here we found that after infection with an intestinal nematode, antigen-bearing DCs and CD4(+) T cells upregulated the chemokine receptor CXCR5 and localized together outside the T cell zone by a mechanism dependent on the chemokine CXCL13, B cells and lymphotoxin. Notably, lymphotoxin-expressing B cells, CXCR5-expressing DCs and T cells, and CXCL13 were also necessary for development of interleukin 4 (IL-4)-producing type 2 helper T cells (T(H)2 cells), which suggests that T(H)2 differentiation can initiate outside the T cell zone.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Linfotoxina-alfa/imunologia , Receptores CXCR5/imunologia , Infecções por Strongylida/imunologia , Células Th2/imunologia , Animais , Quimiocina CXCL13/imunologia , Interleucina-4/imunologia , Ativação Linfocitária/imunologia , Linfotoxina-alfa/biossíntese , Linfotoxina-alfa/genética , Camundongos , Camundongos Endogâmicos C57BL , Nematospiroides dubius/imunologia
9.
Immunity ; 41(1): 127-40, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-25035957

RESUMO

Memory CD8(+) T cells are programmed during the primary response for robust secondary responsiveness. Here we show that CD8(+) T cells responding to different epitopes of influenza virus received qualitatively different signals during the primary response that altered their secondary responsiveness. Nucleoprotein (NP)-specific CD8(+) T cells encountered antigen on CD40-licensed, CD70-expressing, CD103(-)CD11b(hi) dendritic cells (DCs) at later times in the primary response. As a consequence, they maintained CD25 expression and responded to interleukin-2 (IL-2) and CD27, which together programmed their robust secondary proliferative capacity and interferon-γ (IFN-γ)-producing ability. In contrast, polymerase (PA)-specific CD8(+) T cells did not encounter antigen-bearing, CD40-activated DCs at later times in the primary response, did not receive CD27 and CD25 signals, and were not programmed to become memory CD8(+) T cells with strong proliferative and cytokine-producing ability. As a result, CD8(+) T cells responding to abundant antigens, like NP, dominated the secondary response.


Assuntos
Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Memória Imunológica/imunologia , Vírus da Influenza A/imunologia , Transferência Adotiva , Animais , Antígenos CD/imunologia , Antígeno CD11b/imunologia , Ligante CD27/biossíntese , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/genética , Antígenos CD40/imunologia , Células Cultivadas , RNA Polimerases Dirigidas por DNA/imunologia , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/farmacologia , Cadeias alfa de Integrinas/imunologia , Interferon gama/biossíntese , Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Subunidade alfa de Receptor de Interleucina-2/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Nucleoproteínas/imunologia , Infecções por Orthomyxoviridae/imunologia , Transdução de Sinais/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Proteínas do Core Viral/imunologia
10.
Nat Immunol ; 11(3): 216-24, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20098442

RESUMO

The question of which dendritic cells (DCs) respond to pulmonary antigens and cross-prime CD8(+) T cells remains controversial. We show here that influenza-specific CD8(+) T cell priming was controlled by different DCs at different times after infection. Whereas early priming was controlled by both CD103(+)CD11b(lo) and CD103(-)CD11b(hi) DCs, CD103(-)CD11b(hi) DCs dominated antigen presentation at the peak of infection. Moreover, CD103(-)CD11b(hi) DCs captured exogenous antigens in the lungs and directly cross-primed CD8(+) T cells in the draining lymph nodes without transferring antigen to CD8alpha(+) DCs. Finally, we show that CD103(-)CD11b(hi) DCs were the only DCs to express CD70 after influenza infection and that CD70 expression on CD103(-)CD11b(hi) DCs licensed them to expand CD8(+) T cell populations responding to both influenza and exogenous ovalbumin.


Assuntos
Ligante CD27/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Animais , Linfócitos T CD4-Positivos/virologia , Apresentação Cruzada/imunologia , Células Dendríticas/virologia , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe II/imunologia , Imunofenotipagem , Cinética , Linfonodos/imunologia , Linfonodos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Nucleocapsídeo/imunologia , Infecções por Orthomyxoviridae/virologia
11.
Immunity ; 36(5): 847-56, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22464171

RESUMO

T follicular helper (Tfh) cells promote T cell-dependent humoral immune responses by providing T cell help to B cells and by promoting germinal center (GC) formation and long-lived antibody responses. However, the cellular and molecular mechanisms that control Tfh cell differentiation in vivo are incompletely understood. Here we show that interleukin-2 (IL-2) administration impaired influenza-specific GCs, long-lived IgG responses, and Tfh cells. IL-2 did not directly inhibit GC formation, but instead suppressed the differentiation of Tfh cells, thereby hindering the maintenance of influenza-specific GC B cells. Our data demonstrate that IL-2 is a critical factor that regulates successful Tfh and B cell responses in vivo and regulates Tfh cell development.


Assuntos
Diferenciação Celular/imunologia , Centro Germinativo/imunologia , Interleucina-2/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Centro Germinativo/citologia , Centro Germinativo/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Orthomyxoviridae/imunologia , Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
12.
J Immunol ; 202(6): 1649-1658, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30833421

RESUMO

Although multiple and overlapping mechanisms are ultimately responsible for the immunopathology observed in patients with systemic lupus erythematosus, autoreactive Abs secreted by autoreactive plasma cells (PCs) are considered to play a critical role in disease progression and immunopathology. Given that PCs derive from the germinal centers (GC), long-term dysregulated GC reactions are often associated with the development of spontaneous autoantibody responses and immunopathology in systemic lupus erythematosus patients. In this review, we summarize the emerging evidence concerning the roles of T follicular helper cells in regulating pathogenic GC and autoreactive PC responses in lupus.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoanticorpos/imunologia , Centro Germinativo/imunologia , Humanos , Plasmócitos/imunologia
13.
Immunity ; 35(4): 496-8, 2011 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-22035843

RESUMO

The signals that regulate the differentiation of central and effector memory T cells remain unclear. In this issue of Immunity, Pepper et al. (2011) and Marshall et al. (2011) implicate the differential expression of transcription factors in driving memory subtypes.

14.
J Immunol ; 199(7): 2377-2387, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28848064

RESUMO

B cell lymphoma-6 (Bcl-6) is a transcriptional repressor that is required for the differentiation of T follicular helper (TFH) cell populations. Currently, the molecular mechanisms underlying the transcriptional regulation of Bcl-6 expression are unclear. In this study, we have identified the Ikaros zinc finger transcription factors Aiolos and Ikaros as novel regulators of Bcl-6. We found that increased expression of Bcl-6 in CD4+ Th cell populations correlated with enhanced enrichment of Aiolos and Ikaros at the Bcl6 promoter. Furthermore, overexpression of Aiolos or Ikaros, but not the related family member Eos, was sufficient to induce Bcl6 promoter activity. Intriguingly, STAT3, a known Bcl-6 transcriptional regulator, physically interacted with Aiolos to form a transcription factor complex capable of inducing the expression of Bcl6 and the TFH-associated cytokine receptor Il6ra Importantly, in vivo studies revealed that the expression of Aiolos was elevated in Ag-specific TFH cells compared with that observed in non-TFH effector Th cells generated in response to influenza infection. Collectively, these data describe a novel regulatory mechanism through which STAT3 and the Ikaros zinc finger transcription factors Aiolos and Ikaros cooperate to regulate Bcl-6 expression.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Fator de Transcrição Ikaros/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Fator de Transcrição STAT3/metabolismo , Animais , Diferenciação Celular , Regulação da Expressão Gênica , Fator de Transcrição Ikaros/genética , Camundongos , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fator de Transcrição STAT3/genética , Linfócitos T Auxiliares-Indutores/metabolismo , Transativadores/genética , Transativadores/metabolismo
15.
J Immunol ; 193(4): 1531-7, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25086176

RESUMO

Although we have known for decades that B cells contribute to immune responses by secreting Ab, it is now clear that they are more than simply factories for Ig production, and they also play key roles as modulators of T cell-dependent immunity. Indeed, the evidence showing that Ag-presenting and cytokine-producing B cells can alter the magnitude and quality of CD4 T cell responses continues to grow. In this article, we review the data showing that B cells, working in partnership with dendritic cells, regulate the development of Th2 cells and the subsequent allergic response.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Hipersensibilidade/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos
16.
Immunol Cell Biol ; 92(1): 22-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24145854

RESUMO

T follicular helper cells (Tfh) are required to generate long-lived antibody responses, which confer long-term protection to pathogens following vaccination or infection. Despite significant advances in the field, however, little is known about the early steps that drive Tfh cell differentiation. In this review, we will discuss the mechanisms by which dendritic cells promote the initial commitment of activated CD4(+) T cells to the Tfh cell differentiation pathway.


Assuntos
Diferenciação Celular , Células Dendríticas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Humanos
17.
Cell Mol Immunol ; 20(6): 651-665, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37046042

RESUMO

Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE levels. However, the underlying mechanism by which IL-6 prevents the development of Th2-driven diseases remains unknown. Using a model of house dust mite (HDM)-induced Th2 cell differentiation and allergic airway inflammation, we showed that IL-6 signaling in allergen-specific T cells was required to prevent Th2 cell differentiation and the subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. We found that IL-6 turned off IL-2 signaling during early T-cell activation and thus inhibited Th2 priming. Mechanistically, IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of Suppressor Of Cytokine Signaling 3 (SOCS3). This mechanism could be mimicked by pharmacological Janus Kinase-1 (JAK1) inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.


Assuntos
Interleucina-6 , Células Th2 , Humanos , Células Th2/metabolismo , Interleucina-2 , Inflamação , Imunoglobulina E , Citocinas/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas
18.
Methods Mol Biol ; 2380: 189-199, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34802132

RESUMO

Within the last several years, great strides have been made in understanding the molecular and cellular mechanisms that control the generation of T follicular helper (TFH), T regulatory (TREG), and T follicular regulatory (TFR) cells. As a result, it is now clear that cytokines play a critical role in regulating the development and function of these CD4+ T cell subsets. One of the critical limitations when studying the effect of individual cytokines in these populations is differentiating between the intrinsic and extrinsic effects of these cytokines in vivo. Here we describe how to utilize mixed bone marrow chimeras in combination with MHC class II tetramers to characterize the direct role played by cytokines on controlling the development, function, and maintenance of TFH, TREG, and TFR cells in vivo.


Assuntos
Influenza Humana , Citocinas , Humanos , Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores
19.
Front Immunol ; 12: 667342, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986755

RESUMO

Immunosuppressive drugs can partially control Antibody (Ab)-dependent pathology. However, these therapeutic regimens must be maintained for the patient's lifetime, which is often associated with severe side effects. As research advances, our understanding of the cellular and molecular mechanisms underlying the development and maintenance of auto-reactive B cell responses has significantly advanced. As a result, novel immunotherapies aimed to restore immune tolerance and prevent disease progression in autoimmune patients are underway. In this regard, encouraging results from clinical and preclinical studies demonstrate that subcutaneous administration of low-doses of recombinant Interleukin-2 (r-IL2) has potent immunosuppressive effects in patients with autoimmune pathologies. Although the exact mechanism by which IL-2 induces immunosuppression remains unclear, the clinical benefits of the current IL-2-based immunotherapies are attributed to its effect on bolstering T regulatory (Treg) cells, which are known to suppress overactive immune responses. In addition to Tregs, however, rIL-2 also directly prevent the T follicular helper cells (Tfh), T helper 17 cells (Th17), and Double Negative (DN) T cell responses, which play critical roles in the development of autoimmune disorders and have the ability to help pathogenic B cells. Here we discuss the broader effects of rIL-2 immunotherapy and the potential of combining rIL-2 with other cytokine-based therapies to more efficiently target Tfh cells, Th17, and DN T cells and subsequently inhibit auto-antibody (ab) production in autoimmune patients.


Assuntos
Doenças Autoimunes/terapia , Linfócitos B/imunologia , Interleucina-2/uso terapêutico , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/imunologia , Humanos , Imunidade Humoral , Memória Imunológica , Terapia de Imunossupressão , Imunoterapia , Interleucina-2/imunologia , Camundongos
20.
Front Immunol ; 12: 637948, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33643321

RESUMO

It is estimated that more than 339 million people worldwide suffer from asthma. The leading cause of asthma development is the breakdown of immune tolerance to inhaled allergens, prompting the immune system's aberrant activation. During the early phase, also known as the sensitization phase, allergen-specific T cells are activated and become central players in orchestrating the subsequent development of allergic asthma following secondary exposure to the same allergens. It is well-established that allergen-specific T helper 2 (Th2) cells play central roles in developing allergic asthma. As such, 80% of children and 60% of adult asthma cases are linked to an unwarranted Th2 cell response against respiratory allergens. Thus, targeting essential components of Th2-type inflammation using neutralizing antibodies against key Th2 modulators has recently become an attractive option for asthmatic patients with moderate to severe symptoms. In addition to directly targeting Th2 mediators, allergen immunotherapy, also known as desensitization, is focused on redirecting the allergen-specific T cells response from a Th2-type profile to a tolerogenic one. This review highlights the current understanding of the heterogeneity of the Th2 cell compartment, their contribution to allergen-induced airway inflammation, and the therapies targeting the Th2 cell pathway in asthma. Further, we discuss available new leads for successful targeting pulmonary Th2 cell responses for future therapeutics.


Assuntos
Anticorpos Bloqueadores/uso terapêutico , Asma/imunologia , Dessensibilização Imunológica/métodos , Pneumonia/imunologia , Células Th1/imunologia , Animais , Asma/terapia , Humanos , Tolerância Imunológica , Imunomodulação , Pneumonia/terapia , Células Th2/imunologia
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