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1.
Cell ; 169(6): 1119-1129.e11, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552347

RESUMO

The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of Tregs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.


Assuntos
Folículo Piloso/citologia , Células-Tronco/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Células Epiteliais/metabolismo , Folículo Piloso/metabolismo , Humanos , Inflamação/metabolismo , Proteína Jagged-1/metabolismo , Camundongos
2.
Immunity ; 43(5): 1011-21, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26588783

RESUMO

The skin is a site of constant dialog between the immune system and commensal bacteria. However, the molecular mechanisms that allow us to tolerate the presence of skin commensals without eliciting destructive inflammation are unknown. Using a model system to study the antigen-specific response to S. epidermidis, we demonstrated that skin colonization during a defined period of neonatal life was required for establishing immune tolerance to commensal microbes. This crucial window was characterized by an abrupt influx of highly activated regulatory T (Treg) cells into neonatal skin. Selective inhibition of this Treg cell wave completely abrogated tolerance. Thus, the host-commensal relationship in the skin relied on a unique Treg cell population that mediated tolerance to bacterial antigens during a defined developmental window. This suggests that the cutaneous microbiome composition in neonatal life is crucial in shaping adaptive immune responses to commensals, and disrupting these interactions might have enduring health implications.


Assuntos
Animais Recém-Nascidos/imunologia , Pele/imunologia , Pele/microbiologia , Infecções Estafilocócicas/imunologia , Staphylococcus epidermidis/imunologia , Linfócitos T Reguladores/imunologia , Animais , Animais Recém-Nascidos/microbiologia , Antígenos de Bactérias/imunologia , Interações Hospedeiro-Patógeno/imunologia , Tolerância Imunológica/imunologia , Inflamação/imunologia , Inflamação/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/imunologia , Dados de Sequência Molecular , Infecções Estafilocócicas/microbiologia , Linfócitos T Reguladores/microbiologia
3.
J Immunol ; 203(3): 639-646, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31209102

RESUMO

Signaling through CD27 plays a role in T cell activation and memory. However, it is currently unknown how this costimulatory receptor influences CD4+ effector T (Teff) cells in inflamed tissues. In the current study, we used a murine model of inducible self-antigen expression in the epidermis to elucidate the functional role of CD27 on autoreactive Teff cells. Expression of CD27 on Ag-specific Teff cells resulted in enhanced skin inflammation when compared with CD27-deficient Teff cells. CD27 signaling promoted the accumulation of IFN-γ and IL-2-producing T cells in skin draining lymph nodes in a cell-intrinsic fashion. Surprisingly, this costimulatory pathway had minimal effect on early T cell activation and proliferation. Instead, signaling through CD27 resulted in the progressive survival of Teff cells during the autoimmune response. Using BH3 profiling to assess mitochondrial cell priming, we found that CD27-deficient cells were equally as sensitive as CD27-sufficient cells to mitochondrial outer membrane polarization upon exposure to either BH3 activator or sensitizer peptides. In contrast, CD27-deficient Teff cells expressed higher levels of active caspase 8. Taken together, these results suggest that CD27 does not promote Teff cell survival by increasing expression of antiapoptotic BCL2 family members but instead acts by preferentially suppressing the cell-extrinsic apoptosis pathway, highlighting a previously unidentified role for CD27 in augmenting autoreactive Teff cell responses.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Epiderme/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Transferência Adotiva , Animais , Apoptose/fisiologia , Autoimunidade/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Caspase 8/metabolismo , Proliferação de Células/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Memória Imunológica/imunologia , Inflamação/imunologia , Interferon gama/metabolismo , Interleucina-2/metabolismo , Linfonodos/imunologia , Ativação Linfocitária/imunologia , Potencial da Membrana Mitocondrial/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Modelos Animais , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
4.
J Immunol ; 200(9): 3100-3108, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29563179

RESUMO

Migratory dendritic cell (DC) subsets deliver tissue Ags to draining lymph nodes (DLNs) to either initiate or inhibit T cell-mediated immune responses. The signals mediating DC migration in response to tissue self-antigen are largely unknown. Using a mouse model of inducible skin-specific self-antigen expression, we demonstrate that CD103+ dermal DCs (DDCs) rapidly migrate from skin to skin DLN (SDLNs) within the first 48 h after Ag expression. This window of time was characterized by the preferential activation of tissue-resident Ag-specific effector T cells (Teffs), with no concurrent activation of Ag-specific Teffs in SDLNs. Using genetic deletion and adoptive transfer approaches, we show that activation of skin-resident Teffs is required to drive CD103+ DDC migration in response to tissue self-antigen and this Batf3-dependent DC population is necessary to mount a fulminant autoimmune response in skin. Conversely, activation of Ag-specific Teffs in SDLNs played no role in DDC migration. Our studies reveal a crucial role for skin-resident T cell-derived signals, originating at the site of self-antigen expression, to drive DDC migration during the elicitation phase of an autoimmune response.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Células de Langerhans/imunologia , Linfócitos T/imunologia , Animais , Movimento Celular/imunologia , Linfonodos/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Pele/citologia , Pele/imunologia
5.
J Immunol ; 196(5): 2010-4, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26826250

RESUMO

Foxp3-expressing regulatory T cells (Tregs) reside in tissues where they control inflammation and mediate tissue-specific functions. The skin of mice and humans contain a large number of Tregs; however, the mechanisms of how these cells function in skin remain largely unknown. In this article, we show that Tregs facilitate cutaneous wound healing. Highly activated Tregs accumulated in skin early after wounding, and specific ablation of these cells resulted in delayed wound re-epithelialization and kinetics of wound closure. Tregs in wounded skin attenuated IFN-γ production and proinflammatory macrophage accumulation. Upon wounding, Tregs induce expression of the epidermal growth factor receptor (EGFR). Lineage-specific deletion of EGFR in Tregs resulted in reduced Treg accumulation and activation in wounded skin, delayed wound closure, and increased proinflammatory macrophage accumulation. Taken together, our results reveal a novel role for Tregs in facilitating skin wound repair and suggest that they use the EGFR pathway to mediate these effects.


Assuntos
Receptores ErbB/imunologia , Linfócitos T Reguladores/imunologia , Cicatrização/imunologia , Animais , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/imunologia
6.
J Immunol ; 192(4): 1351-5, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24442443

RESUMO

Immune homeostasis in peripheral tissues is achieved by maintaining a balance between pathogenic effector T cells (Teffs) and protective Foxp3(+) regulatory T cells (Tregs). Using a mouse model of an inducible tissue Ag, we demonstrate that Ag persistence is a major determinant of the relative frequencies of Teffs and Tregs. Encounter of transferred naive CD4(+) T cells with transiently expressed tissue Ag leads to generation of cytokine-producing Teffs and peripheral Tregs. Persistent expression of Ag, a mimic of self-antigen, leads to functional inactivation and loss of the Teffs with preservation of Tregs in the target tissue. The inactivation of Teffs by persistent Ag is associated with reduced ERK phosphorylation, whereas Tregs show less reduction in ERK phosphorylation and are relatively resistant to ERK inhibition. Our studies reveal a crucial role for Ag in maintaining appropriate ratios of Ag-specific Teffs to Tregs in tissues.


Assuntos
Autoantígenos/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Benzamidas/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Difenilamina/análogos & derivados , Difenilamina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Inflamação/imunologia , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Ovalbumina , Fosforilação , Pele/imunologia , Linfócitos T Reguladores/transplante
7.
J Immunol ; 190(9): 4483-7, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23543753

RESUMO

Thymic Foxp3-expressing regulatory T cells are activated by peripheral self-antigen to increase their suppressive function, and a fraction of these cells survive as memory regulatory T cells (mTregs). mTregs persist in nonlymphoid tissue after cessation of Ag expression and have enhanced capacity to suppress tissue-specific autoimmunity. In this study, we show that murine mTregs express specific effector memory T cell markers and localize preferentially to hair follicles in skin. Memory Tregs express high levels of both IL-2Rα and IL-7Rα. Using a genetic-deletion approach, we show that IL-2 is required to generate mTregs from naive CD4(+) T cell precursors in vivo. However, IL-2 is not required to maintain these cells in the skin and skin-draining lymph nodes. Conversely, IL-7 is essential for maintaining mTregs in skin in the steady state. These results elucidate the fundamental biology of mTregs and show that IL-7 plays an important role in their survival in skin.


Assuntos
Memória Imunológica/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Receptores de Interleucina-7/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos/imunologia , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Folículo Piloso/imunologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pele/imunologia
8.
J Immunol ; 191(2): 535-9, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23785118

RESUMO

Psoriasis is a chronic, inflammatory skin disease caused by a combination of environmental and genetic factors. The Tnip1 gene encodes A20 binding and inhibitor of NF-κB-1 (ABIN-1) protein and is strongly associated with susceptibility to psoriasis in humans. ABIN-1, a widely expressed ubiquitin-binding protein, restricts TNF- and TLR-induced signals. In this study, we report that mice lacking ABIN-1 specifically in dendritic cells (DCs), ABIN-1(fl) CD11c-Cre mice, exhibit perturbed immune homeostasis. ABIN-1-deficient DCs display exaggerated NF-κB and MAPK signaling and produce more IL-23 than do normal cells in response to TLR ligands. Challenge of ABIN-1(fl) CD11c-Cre mice with topical TLR7 ligand leads to greater numbers of Th17 and TCRγδ T cells and exacerbated development of psoriaform lesions. These phenotypes are reversed by DC-specific deletion of the TLR adaptor MyD88. These studies link ABIN-1 with IL-23 and IL-17, and they provide cellular and molecular mechanisms by which ABIN-1 regulates susceptibility to psoriasis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Células Dendríticas/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Psoríase/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Células Cultivadas , Células Dendríticas/imunologia , Suscetibilidade a Doenças , Inflamação , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/metabolismo , Psoríase/genética , Psoríase/metabolismo , Transdução de Sinais , Células Th17/imunologia , Receptor 7 Toll-Like/metabolismo
9.
Sci Rep ; 13(1): 8671, 2023 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-37248279

RESUMO

People are widely exposed to polycyclic aromatic hydrocarbons, like benzo[a]pyrene (BaP). Prior studies showed that prenatal exposure to BaP depletes germ cells in ovaries, causing earlier onset of ovarian senescence post-natally; developing testes were affected at higher doses than ovaries. Our primary objective was to determine if prenatal BaP exposure results in transgenerational effects on ovaries and testes. We orally dosed pregnant germ cell-specific EGFP-expressing mice (F0) with 0.033, 0.2, or 2 mg/kg-day BaP or vehicle from embryonic day (E) 6.5-11.5 (F1 offspring) or E6.5-15.5 (F2 and F3). Ovarian germ cells at E13.5 and follicle numbers at postnatal day 21 were significantly decreased in F3 females at all doses of BaP; testicular germ cell numbers were not affected. E13.5 germ cell RNA-sequencing revealed significantly increased expression of male-specific genes in female germ cells across generations and BaP doses. Next, we compared the ovarian effects of 2 mg/kg-day BaP dosing to wild type C57BL/6J F0 dams from E6.5-11.5 or E12.5-17.5. We observed no effects on F3 ovarian follicle numbers with either of the shorter dosing windows. Our results demonstrate that F0 BaP exposure from E6.5-15.5 decreased the number of and partially disrupted transcriptomic sexual identity of female germ cells transgenerationally.


Assuntos
Reserva Ovariana , Efeitos Tardios da Exposição Pré-Natal , Gravidez , Humanos , Camundongos , Masculino , Feminino , Animais , Ovário/metabolismo , Benzo(a)pireno/metabolismo , Transcriptoma , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Camundongos Endogâmicos C57BL , Células Germinativas
10.
Cell Host Microbe ; 21(4): 467-477.e5, 2017 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-28343820

RESUMO

Regulatory T cells (Tregs) are required to establish immune tolerance to commensal microbes. Tregs accumulate abruptly in the skin during a defined window of postnatal tissue development. However, the mechanisms mediating Treg migration to neonatal skin are unknown. Here we show that hair follicle (HF) development facilitates the accumulation of Tregs in neonatal skin and that upon skin entry these cells localize to HFs, a primary reservoir for skin commensals. Further, germ-free neonates had reduced skin Tregs indicating that commensal microbes augment Treg accumulation. We identified Ccl20 as a HF-derived, microbiota-dependent chemokine and found its receptor, Ccr6, to be preferentially expressed by Tregs in neonatal skin. The Ccl20-Ccr6 pathway mediated Treg migration in vitro and in vivo. Thus, HF morphogenesis, commensal microbe colonization, and local chemokine production work in concert to recruit Tregs into neonatal skin, thereby establishing this tissue Treg niche early in life.


Assuntos
Folículo Piloso/crescimento & desenvolvimento , Microbiota/imunologia , Morfogênese , Pele/imunologia , Pele/microbiologia , Simbiose , Linfócitos T Reguladores/imunologia , Animais , Quimiocina CCL20/metabolismo , Folículo Piloso/imunologia , Folículo Piloso/microbiologia , Tolerância Imunológica , Camundongos , Receptores CCR6/metabolismo
11.
J Clin Invest ; 124(3): 1027-36, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24509084

RESUMO

Regulatory T cells (Tregs), which are characterized by expression of the transcription factor Foxp3, are a dynamic and heterogeneous population of cells that control immune responses and prevent autoimmunity. We recently identified a subset of Tregs in murine skin with properties typical of memory cells and defined this population as memory Tregs (mTregs). Due to the importance of these cells in regulating tissue inflammation in mice, we analyzed this cell population in humans and found that almost all Tregs in normal skin had an activated memory phenotype. Compared with mTregs in peripheral blood, cutaneous mTregs had unique cell surface marker expression and cytokine production. In normal human skin, mTregs preferentially localized to hair follicles and were more abundant in skin with high hair density. Sequence comparison of TCRs from conventional memory T helper cells and mTregs isolated from skin revealed little homology between the two cell populations, suggesting that they recognize different antigens. Under steady-state conditions, mTregs were nonmigratory and relatively unresponsive; however, in inflamed skin from psoriasis patients, mTregs expanded, were highly proliferative, and produced low levels of IL-17. Taken together, these results identify a subset of Tregs that stably resides in human skin and suggest that these cells are qualitatively defective in inflammatory skin disease.


Assuntos
Folículo Piloso/patologia , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Animais , Antígenos CD/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Feminino , Fatores de Transcrição Forkhead/metabolismo , Folículo Piloso/imunologia , Humanos , Memória Imunológica , Interleucina-17/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Fenótipo , Psoríase/imunologia , Psoríase/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CCR7/metabolismo , Pele/imunologia , Linfócitos T Reguladores/imunologia , Adulto Jovem
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