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1.
Cell Rep ; 38(2): 110209, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35021099

RESUMO

Innate-like T cells, including invariant natural killer T cells, mucosal-associated invariant T cells, and γδ T cells, are present in various barrier tissues, including the lung, where they carry out protective responses during infections. Here, we investigate their roles during pulmonary pneumococcal infection. Following infection, innate-like T cells rapidly increase in lung tissue, in part through recruitment, but T cell antigen receptor activation and cytokine production occur mostly in interleukin-17-producing NKT17 and γδ T cells. NKT17 cells are preferentially located within lung tissue prior to infection, as are CD103+ dendritic cells, which are important both for antigen presentation to NKT17 cells and γδ T cell activation. Whereas interleukin-17-producing γδ T cells are numerous, granulocyte-macrophage colony-stimulating factor is exclusive to NKT17 cells and is required for optimal protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Animais , Linhagem Celular , Células Dendríticas/imunologia , Feminino , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções Pneumocócicas/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Streptococcus pneumoniae/imunologia
2.
J Invest Dermatol ; 140(1): 132-142.e3, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260672

RESUMO

The cell adhesion molecule E-cadherin is a major component of adherens junctions and marks Langerhans cells (LC), the only dendritic cell (DC) population of the epidermis. LC form a dense network and attach themselves to the surrounding keratinocytes via homophilic E-cadherin binding. LC activation, mobilization, and migration require a reduction in LC E-cadherin expression. To determine whether E-cadherin plays a role in regulating LC homeostasis and function, we generated CD11c-specific E-cadherin knockout mice (CD11c-Ecaddel). In the absence of E-cadherin-mediated cell adhesion, LC numbers remained stable and similar as in control mice, even in aged animals. Intriguingly, E-cadherin-deficient LC displayed a dramatically changed morphology characterized by a more rounded cell body and fewer dendrites than wild-type cells. Nevertheless, maturation and migration of LC lacking E-cadherin was not altered, neither under steady-state nor inflammatory conditions. Accordingly, CD11c-Ecaddel and control mice developed comparable contact hypersensitivity reactions and imiquimod-triggered psoriatic skin inflammation, indicating that E-cadherin on LC does not influence their ability to orchestrate T cell-mediated immunity. In conclusion, our data demonstrate that E-cadherin is dispensable to maintain LC in the epidermis and does not regulate LC maturation, migration, and function.


Assuntos
Caderinas/metabolismo , Dermatite de Contato/imunologia , Epiderme/fisiologia , Células de Langerhans/fisiologia , Psoríase/imunologia , Animais , Antígeno CD11c/genética , Antígeno CD11c/metabolismo , Caderinas/genética , Diferenciação Celular , Movimento Celular , Forma Celular , Células Cultivadas , Dermatite de Contato/genética , Modelos Animais de Doenças , Homeostase , Humanos , Imiquimode , Camundongos , Camundongos Knockout , Psoríase/genética
3.
Gastroenterology ; 146(7): 1752-62.e4, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24560868

RESUMO

BACKGROUND & AIMS: The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Expression of the tumor necrosis factor (TNF) superfamily member 14 (TNFSF14, also known as LIGHT [homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes]) on T cells is involved in their activation; transgenic expression of LIGHT on T cells in mice promotes inflammation in multiple organs, including intestine. We investigated the roles for LIGHT in recovery from intestinal inflammation in mice. METHODS: We studied the role of LIGHT in intestinal inflammation using Tnfsf14(-/-) and wild-type mice. Colitis was induced by transfer of CD4(+)CD45RB(high) T cells into Rag1(-/-) or Tnfsf14(-/-)Rag1(-/-) mice, or by administration of dextran sulfate sodium to Tnfsf14(-/-) or wild-type C57BL/6J mice. Mice were weighed, colon tissues were collected and measured, and histology analyses were performed. We measured infiltrating cell populations and expression of cytokines, chemokines, and LIGHT. RESULTS: After administration of dextran sulfate sodium, Tnfsf14(-/-) mice developed more severe colitis than controls, based on their reduced survival, accelerated loss of body weight, and histologic scores. LIGHT protected mice from colitis via the lymphotoxin ß receptor and was expressed mainly by myeloid cells in the colon. Colons of Tnfsf14(-/-) mice also had increased accumulation of innate immune cells and higher levels of cytokines than colons from control mice. LIGHT, therefore, appears to regulate inflammation in the colon. CONCLUSIONS: Tnfsf14(-/-) mice develop more severe colitis than control mice. LIGHT signals through the lymphotoxin ß receptor in the colon to regulate the innate immune response and mediate recovery from intestinal inflammation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Colite/metabolismo , Colo/metabolismo , Mucosa Intestinal/metabolismo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/transplante , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colite/prevenção & controle , Colo/imunologia , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Imunidade Inata , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Antígenos Comuns de Leucócito/metabolismo , Receptor beta de Linfotoxina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Índice de Gravidade de Doença , Transdução de Sinais , Fatores de Tempo , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/deficiência , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Redução de Peso
4.
J Leukoc Biol ; 95(1): 179-90, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24023259

RESUMO

Whereas CD8⁺ T cells are essential for anti-tumor immunity, tumors often evade CD8⁺ T cell surveillance by immunosuppression. As the initiators of antigen-specific immune responses, DCs are likely to play a central role in regulating the balance between immunity and tolerance to tumor antigens and are specialized in their ability to cross-present exogenous tumor antigens on MHC class I molecules to initiate CD8⁺ T cell immunity. However, it remains unclear whether and how tumors modulate DC functions to suppress CD8⁺ T cell responses. We have shown previously that ß-catenin signaling in DCs promotes DC-mediated CD8⁺ T cell tolerance. Here, we tested the hypothesis that ß-catenin in DCs mediates tumor-induced suppression of CD8⁺ T cell immunity by inhibiting the ability of DCs in cross-priming. ß-Catenin was activated in DCs by multiple tumors in vivo and in vitro. B16 melanoma-bearing mice, when vaccinated with DC-targeting anti-DEC-205 mAb fused with tumor antigens, exhibited dampened CD8⁺ immunity, similar to DC-ß-catenin(active) mice. DCs from DC-ß-catenin(active) and tumor-bearing mice were deficient in cross-priming, and antigen-specific CD8⁺ T cells primed in these mice resulted in dampened CD8⁺ memory responses. Importantly, DC-ß-catenin⁻/⁻ mice completely abrogate tumor-mediated inhibition of cross-priming, suggesting that tumor-induced inhibition of cross-priming is dependent on ß-catenin. Finally, enhancing cross-priming at the priming or recall phase rescued ß-catenin-suppressed CD8⁺ immunity in DC-ß-catenin(active) and tumor-bearing mice. Thus, ß-catenin-mediated inhibition of cross-priming represents a new and potentially general mechanism that tumors employ to achieve immunosuppression.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Apresentação Cruzada/imunologia , Tolerância Imunológica , Neoplasias/imunologia , Neoplasias/metabolismo , beta Catenina/metabolismo , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Memória Imunológica , Melanoma Experimental , Camundongos , Camundongos Knockout , Neoplasias/genética
5.
Blood ; 123(2): 217-27, 2014 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-24092934

RESUMO

Langerhans cells (LCs) are dendritic cells (DCs) residing in epithelia, where they critically regulate immunity and tolerance. The p14 adaptor molecule is part of the late endosomal/LAMTOR (lysosomal adaptor and mitogen-activated protein kinase and mammalian target of rapamycin [mTOR] activator/regulator) complex, thereby contributing to the signal transduction of the extracellular signaling-regulated kinase (ERK) and the mTOR cascade. Furthermore, p14 represents an important regulator for endosomal sorting processes within the cell. Mutated, dysfunctional p14 leads to a human immunodeficiency disorder with endosomal/lysosomal defects in immune cells. Because p14 participates in the regulation of endosomal trafficking, growth factor signaling, and cell proliferation, we investigated the role of p14 in mouse DCs/LCs using a conditional knockout mouse model. p14-deficient animals displayed a virtually complete loss of LCs in the epidermis early after birth due to impaired proliferation and increased apoptosis of LCs. Repopulation analysis after application of contact sensitizer leads to the recruitment of a transient LC population, predominantly consisting of short-term LCs. The underlying molecular mechanism involves the p14-mediated disruption of the LAMTOR complex which results in the malfunction of both ERK and mTOR signal pathways. Hence, we conclude that p14 acts as a novel and essential regulator of LC homeostasis in vivo.


Assuntos
Endossomos/metabolismo , Homeostase , Células de Langerhans/metabolismo , Proteínas/genética , Proteínas/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/genética , Antígeno CD11c/genética , Antígeno CD11c/metabolismo , Proliferação de Células , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Knockout , Mitose/genética , Complexos Multiproteicos/metabolismo , Transdução de Sinais , Pele/imunologia , Pele/metabolismo , Pele/patologia , Serina-Treonina Quinases TOR/metabolismo
6.
J Exp Med ; 210(9): 1657-64, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23940255

RESUMO

Langerhans cells (LCs) constitute a network of immune sentinels in the skin epidermis that is seeded during embryogenesis. Whereas the development of LCs has been extensively studied, much less is known about the homeostatic renewal of adult LCs in "nonmanipulated" animals. Here, we present a new multicolor fluorescent fate mapping system and quantification approach to investigate adult LC homeostasis. This novel approach enables us to propose and provide evidence for a model in which the adult epidermal LC network is not formed by mature coequal LCs endowed with proliferative capabilities, but rather constituted by adjacent proliferative units composed of "dividing" LCs and their terminally differentiated daughter cells. Altogether, our results demonstrate the general utility of our novel fate-mapping system to follow cell population dynamics in vivo and to establish an alternative model for LC homeostasis.


Assuntos
Linhagem da Célula , Técnicas Citológicas/métodos , Homeostase , Células de Langerhans/patologia , Animais , Cor , Imageamento Tridimensional , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
7.
Proc Natl Acad Sci U S A ; 110(26): 10723-8, 2013 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-23754427

RESUMO

Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c(+) DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin(+) DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin(neg) DCs in vivo. In conclusion, TLR7-activated Langerin(neg) cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.


Assuntos
Antígenos de Superfície/genética , Interleucina-23/biossíntese , Células de Langerhans/imunologia , Lectinas Tipo C/deficiência , Lectinas Tipo C/genética , Lectinas de Ligação a Manose/deficiência , Lectinas de Ligação a Manose/genética , Psoríase/imunologia , Aminoquinolinas/administração & dosagem , Animais , Antígenos de Superfície/biossíntese , Modelos Animais de Doenças , Imiquimode , Células de Langerhans/efeitos dos fármacos , Lectinas Tipo C/biossíntese , Lectinas de Ligação a Manose/biossíntese , Glicoproteínas de Membrana/agonistas , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Psoríase/etiologia , Psoríase/patologia , Receptor 7 Toll-Like/agonistas
8.
J Immunol ; 187(10): 5069-76, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21998450

RESUMO

The critical role of Langerhans cells (LC) in contact hypersensitivity (CHS) was recently questioned in studies using different LC-depletion mouse models. On one hand, inducible ablation of LC led to diminished ear swelling, suggesting functional redundancy between LC and (Langerin(+)) dermal dendritic cells (DC). On the other hand, constitutive or acute depletion of LC resulted in an enhanced reaction, supporting a regulatory role of LC in CHS. To address this controversy by conditional gene targeting, we generated Langerin-Cre knockin mice. Breeding these mice to a Cre-reporter strain demonstrated robust and specific DNA recombination in LC, as well as other Langerin(+) tissue DC. In agreement with the vital requirement of TGF-ß signaling for LC development, crossing Langerin-Cre to mice homozygous for a loxP-flanked TGF-ßR1 allele resulted in permanent LC deficiency, whereas the homeostasis of dermal Langerin(+) DC was unaffected. In the absence of LC, induction of CHS in these Langerin(+) DC-specific TGF-ßR1-deficient mice elicited decreased ear swelling compared with controls. This novel approach provided further evidence against a regulatory function of LC in CHS. Moreover, these Langerin-Cre mice represent a unique and powerful tool to dissect the role and molecular control of Langerin(+) DC populations beyond LC.


Assuntos
Antígenos CD/genética , Dermatite Alérgica de Contato/imunologia , Deleção de Genes , Integrases/genética , Células de Langerhans/imunologia , Lectinas Tipo C/deficiência , Lectinas Tipo C/genética , Lectinas de Ligação a Manose/deficiência , Lectinas de Ligação a Manose/genética , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Receptores de Fatores de Crescimento Transformadores beta/genética , Animais , Antígenos CD/biossíntese , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Dermatite Alérgica de Contato/genética , Dermatite Alérgica de Contato/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Técnicas de Introdução de Genes/métodos , Marcação de Genes , Células de Langerhans/enzimologia , Células de Langerhans/patologia , Lectinas Tipo C/biossíntese , Lectinas de Ligação a Manose/biossíntese , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/fisiologia , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/fisiologia
9.
J Immunol ; 187(6): 3104-10, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21844385

RESUMO

An immunoregulatory role of aryl hydrocarbon receptor (AhR) has been shown in conventional αß and γδ T cells, but its function in skin γδ T cells (dendritic epidermal T cells [DETC]) is unknown. In this study, we demonstrate that DETC express AhR in wild-type mice, and are specifically absent in the epidermis of AhR-deficient mice (AhR-KO). We show that DETC precursors are generated in the thymus and home to the skin. Proliferation of DETC in the skin was impaired in AhR-KO mice, resulting in a >90% loss compared with wild type. Surprisingly, DETC were not replaced by αß T cells or conventional γδ T cells, suggesting a limited time frame for seeding this niche. We found that DETC from AhR-KO mice failed to express the receptor tyrosine kinase c-Kit, a known growth factor for γδ T cells in the gut. Moreover, we found that c-kit is a direct target of AhR, and propose that AhR-dependent c-Kit expression is potentially involved in DETC homeostasis. DETC are a major source of GM-CSF in the skin. Recently, we had shown that impaired Langerhans cell maturation in AhR-KO is related to low GM-CSF levels. Our findings suggest that the DETCs are necessary for LC maturation, and provide insights into a novel role for AhR in the maintenance of skin-specific γδ T cells, and its consequences for the skin immune network.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Epiderme/imunologia , Homeostase/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Linfócitos T/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Separação Celular , Células Epidérmicas , Epiderme/metabolismo , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/metabolismo
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