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1.
J Immunol ; 210(5): 618-627, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36602520

RESUMO

Innate lymphoid cells (ILCs) are capable of rapid response to a wide variety of immune challenges, including various respiratory pathogens. Despite this, their role in the immune response against the lethal intracellular bacterium Francisella tularensis is not yet known. In this study, we demonstrate that infection of the airways with F. tularensis results in a significant reduction in lung type 2 ILCs (ILC2s) in mice. Conversely, the expansion of ILC2s via treatment with the cytokine IL-33, or by adoptive transfer of ILC2s, resulted in significantly enhanced bacterial burdens in the lung, liver, and spleen, suggesting that ILC2s may favor severe infection. Indeed, specific reduction of ILC2s in a transgenic mouse model results in a reduction in lung bacterial burden. Using an in vitro culture system, we show that IFN-γ from the live vaccine strain-infected lung reduces ILC2 numbers, suggesting that this cytokine in the lung environment is mechanistically important in reducing ILC2 numbers during infection. Finally, we show Ab-mediated blockade of IL-5, of which ILC2s are a major innate source, reduces bacterial burden postinfection, suggesting that IL-5 production by ILC2s may play a role in limiting protective immunity. Thus, overall, we highlight a negative role for ILC2s in the control of infection with F. tularensis. Our work therefore highlights the role of ILC2s in determining the severity of potentially fatal airway infections and raises the possibility of interventions targeting innate immunity during infection with F. tularensis to benefit the host.


Assuntos
Francisella tularensis , Animais , Camundongos , Imunidade Inata , Linfócitos , Interleucina-5 , Citocinas
2.
Immunity ; 42(5): 903-15, 2015 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-25979421

RESUMO

Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvß8, which enables them to activate latent transforming growth factor-ß (TGF-ß). Treg-cell-specific deletion of integrin αvß8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvß8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-ß in suppression of self-harmful T cell responses during active inflammation.


Assuntos
Inflamação/imunologia , Integrinas/metabolismo , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Proliferação de Células , Colite/imunologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Humanos , Mediadores da Inflamação/imunologia , Integrinas/genética , Camundongos , Modelos Imunológicos , Linfócitos T Reguladores/citologia
3.
J Biol Chem ; 293(22): 8543-8553, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29581231

RESUMO

Cross-talk between different components of the intestinal barrier and the immune system may be important in maintaining gut homeostasis. A crucial part of the gut barrier is the mucus layer, a cross-linked gel on top of the intestinal epithelium that consists predominantly of the mucin glycoprotein MUC2. However, whether the mucin layer actively regulates intestinal immune cell responses is not clear. Because recent evidence suggests that intestinal dendritic cells (DCs) may be regulated by the mucus layer, we purified intestinal mucin, incubated it with human DCs, and determined the functional effects. Here we show that expression of the chemokine IL-8 and co-stimulatory DC markers CD86 and CD83 are significantly up-regulated on human DCs in the presence of intestinal mucins. Additionally, mucin-exposed DCs promoted neutrophil migration in an IL-8-dependent manner. The stimulatory effects of mucins on DCs were not due to mucin sample contaminants such as lipopolysaccharide, DNA, or contaminant proteins. Instead, mucin glycans are important for the pro-inflammatory effects on DCs. Thus, intestinal mucins are capable of inducing important pro-inflammatory functions in DCs, which could be important in driving inflammatory responses upon intestinal barrier damage.


Assuntos
Células Dendríticas/metabolismo , Interleucina-8/metabolismo , Mucosa Intestinal/metabolismo , Mucinas/farmacologia , Polissacarídeos/química , Animais , Células Cultivadas , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Glicosilação , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/metabolismo
4.
PLoS Pathog ; 9(10): e1003675, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24098124

RESUMO

Chronic intestinal parasite infection is a major global health problem, but mechanisms that promote chronicity are poorly understood. Here we describe a novel cellular and molecular pathway involved in the development of chronic intestinal parasite infection. We show that, early during development of chronic infection with the murine intestinal parasite Trichuris muris, TGFß signalling in CD4+ T-cells is induced and that antibody-mediated inhibition of TGFß function results in protection from infection. Mechanistically, we find that enhanced TGFß signalling in CD4+ T-cells during infection involves expression of the TGFß-activating integrin αvß8 by dendritic cells (DCs), which we have previously shown is highly expressed by a subset of DCs in the intestine. Importantly, mice lacking integrin αvß8 on DCs were completely resistant to chronic infection with T. muris, indicating an important functional role for integrin αvß8-mediated TGFß activation in promoting chronic infection. Protection from infection was dependent on CD4+ T-cells, but appeared independent of Foxp3+ Tregs. Instead, mice lacking integrin αvß8 expression on DCs displayed an early increase in production of the protective type 2 cytokine IL-13 by CD4+ T-cells, and inhibition of this increase by crossing mice to IL-4 knockout mice restored parasite infection. Our results therefore provide novel insights into how type 2 immunity is controlled in the intestine, and may help contribute to development of new therapies aimed at promoting expulsion of gut helminths.


Assuntos
Células Dendríticas/imunologia , Integrinas/imunologia , Enteropatias Parasitárias/imunologia , Células Th2/imunologia , Fator de Crescimento Transformador beta/imunologia , Tricuríase/imunologia , Trichuris/imunologia , Animais , Doença Crônica , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Integrinas/genética , Integrinas/metabolismo , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-13/metabolismo , Enteropatias Parasitárias/genética , Enteropatias Parasitárias/patologia , Camundongos , Camundongos Knockout , Células Th2/metabolismo , Células Th2/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Tricuríase/genética , Tricuríase/metabolismo , Tricuríase/patologia , Trichuris/genética , Trichuris/metabolismo
5.
J Exp Med ; 215(11): 2725-2736, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30355614

RESUMO

Monocytes are crucial immune cells involved in regulation of inflammation either directly or via differentiation into macrophages in tissues. However, many aspects of how their function is controlled in health and disease are not understood. Here we show that human blood monocytes activate high levels of the cytokine TGFß, a pathway that is not evident in mouse monocytes. Human CD14+, but not CD16+, monocytes activate TGFß via expression of the integrin αvß8 and matrix metalloproteinase 14, which dampens their production of TNFα in response to LPS. Additionally, when monocytes differentiate into macrophages, integrin expression and TGFß-activating ability are maintained in anti-inflammatory macrophages but down-regulated in pro-inflammatory macrophages. In the healthy human intestine, integrin αvß8 is highly expressed on mature tissue macrophages, with these cells and their integrin expression being significantly reduced in active inflammatory bowel disease. Thus, our data suggest that integrin αvß8-mediated TGFß activation plays a key role in regulation of monocyte inflammatory responses and intestinal macrophage homeostasis.


Assuntos
Tolerância Imunológica , Doenças Inflamatórias Intestinais/imunologia , Integrinas/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Fator de Crescimento Transformador beta/imunologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Doenças Inflamatórias Intestinais/patologia , Intestinos/imunologia , Intestinos/patologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Fator de Necrose Tumoral alfa/imunologia
6.
Cell Rep ; 17(2): 448-457, 2016 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-27705793

RESUMO

Adult tissue-specific stem cells (SCs) mediate tissue homeostasis and regeneration and can give rise to all lineages in the corresponding tissue, similar to the early progenitors that generate organs in the first place. However, the developmental origins of adult SCs are largely unknown. We recently identified thymosphere-forming stem cells (TSFCs) in the adult mouse thymus, which display genuine stemness features and can generate the two major thymic epithelial cell lineages. Here, we show that embryonic TSFCs possess stemness features but differ from adult TSFCs in surface marker profile. Our findings support the model of a continuous thymic SC lineage that is maintained throughout ontogeny. TGF-ß signaling differentially affects embryonic versus adult thymosphere formation, suggesting that thymic epithelial SC potency depends on both developmental stage and environmental signals. Collectively, our findings suggest that embryonic TSFCs contribute to an adult SC pool and that TSFC plasticity is controlled by TGF-ß signaling.


Assuntos
Células-Tronco Embrionárias/citologia , Células Epiteliais/citologia , Timo/citologia , Fator de Crescimento Transformador beta/genética , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Células-Tronco Embrionárias/metabolismo , Células Epiteliais/metabolismo , Camundongos , Regeneração/genética , Transdução de Sinais , Timo/crescimento & desenvolvimento
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