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1.
Proc Natl Acad Sci U S A ; 115(42): 10738-10743, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30279177

RESUMO

γδ T cells are enriched at barrier sites such as the gut, skin, and lung, where their roles in maintaining barrier integrity are well established. However, how these cells contribute to homeostasis at the gingiva, a key oral barrier and site of the common chronic inflammatory disease periodontitis, has not been explored. Here we demonstrate that the gingiva is policed by γδ T cells with a T cell receptor (TCR) repertoire that diversifies during development. Gingival γδ T cells accumulated rapidly after birth in response to barrier damage, and strikingly, their absence resulted in enhanced pathology in murine models of the oral inflammatory disease periodontitis. Alterations in bacterial communities could not account for the increased disease severity seen in γδ T cell-deficient mice. Instead, gingival γδ T cells produced the wound healing associated cytokine amphiregulin, administration of which rescued the elevated oral pathology of tcrδ-/- mice. Collectively, our results identify γδ T cells as critical constituents of the immuno-surveillance network that safeguard gingival tissue homeostasis.


Assuntos
Anfirregulina/metabolismo , Homeostase , Boca/imunologia , Periodontite/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/fisiologia , Subpopulações de Linfócitos T/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Boca/metabolismo , Periodontite/metabolismo , Periodontite/patologia , Subpopulações de Linfócitos T/metabolismo
2.
J Exp Med ; 221(8)2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38819409

RESUMO

Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis.


Assuntos
Plasticidade Celular , Interleucina-17 , Periodontite , Células Th17 , Células Th17/imunologia , Animais , Periodontite/imunologia , Periodontite/patologia , Plasticidade Celular/imunologia , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , Células T Auxiliares Foliculares/imunologia , Gengiva/imunologia , Gengiva/patologia , Imunoglobulina G/imunologia , Perda do Osso Alveolar/imunologia , Perda do Osso Alveolar/patologia
3.
Eur J Immunol ; 42(12): 3235-42, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22965681

RESUMO

Decline of cell-mediated immunity is often attributed to decaying T-cell numbers and their distribution in peripheral organs. This study examined the hypothesis that qualitative as well as quantitative changes contribute to the declining efficacy of CD8(+) T-cell memory. Using a model of influenza virus infection, where loss of protective CD8(+) T-cell immunity was observed 6 months postinfection, we found no decline in antigen-specific T-cell numbers or migration to the site of secondary infection. There was, however, a large reduction in antigen-specific CD8(+) T-cell degranulation, cytokine secretion, and polyfunctionality. A profound loss of high-avidity T cells over time indicated that failure to confer protective immunity resulted from the inferior functional capacity of remaining low avidity cells. These data imply that high-avidity central memory T cells wane with declining antigen levels, leaving lower avidity T cells with reduced functional capabilities.


Assuntos
Alphainfluenzavirus/imunologia , Degranulação Celular/imunologia , Movimento Celular/imunologia , Imunidade Celular , Memória Imunológica , Infecções por Orthomyxoviridae/imunologia , Animais , Linfócitos T CD8-Positivos , Citocinas/imunologia , Citocinas/metabolismo , Alphainfluenzavirus/metabolismo , Camundongos , Infecções por Orthomyxoviridae/metabolismo , Fatores de Tempo
4.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33635312

RESUMO

Hematopoietic stem cells reside in the bone marrow, where they generate the effector cells that drive immune responses. However, in response to inflammation, some hematopoietic stem and progenitor cells (HSPCs) are recruited to tissue sites and undergo extramedullary hematopoiesis. Contrasting with this paradigm, here we show residence and differentiation of HSPCs in healthy gingiva, a key oral barrier in the absence of overt inflammation. We initially defined a population of gingiva monocytes that could be locally maintained; we subsequently identified not only monocyte progenitors but also diverse HSPCs within the gingiva that could give rise to multiple myeloid lineages. Gingiva HSPCs possessed similar differentiation potentials, reconstitution capabilities, and heterogeneity to bone marrow HSPCs. However, gingival HSPCs responded differently to inflammatory insults, responding to oral but not systemic inflammation. Combined, we highlight a novel pathway of myeloid cell development at a healthy barrier, defining a gingiva-specific HSPC network that supports generation of a proportion of the innate immune cells that police this barrier.


Assuntos
Gengiva/citologia , Gengiva/imunologia , Células Progenitoras Mieloides/citologia , Células Progenitoras Mieloides/imunologia , Animais , Medula Óssea/metabolismo , Feminino , Hematopoese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Bucal/citologia , Mucosa Bucal/imunologia , RNA-Seq/métodos , Análise de Célula Única/métodos
5.
J Exp Med ; 215(6): 1507-1518, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29789388

RESUMO

A defining feature of resident gut macrophages is their high replenishment rate from blood monocytes attributed to tonic commensal stimulation of this site. In contrast, almost all other tissues contain locally maintained macrophage populations, which coexist with monocyte-replenished cells at homeostasis. In this study, we identified three transcriptionally distinct mouse gut macrophage subsets that segregate based on expression of Tim-4 and CD4. Challenging current understanding, Tim-4+CD4+ gut macrophages were found to be locally maintained, while Tim-4-CD4+ macrophages had a slow turnover from blood monocytes; indeed, Tim-4-CD4- macrophages were the only subset with the high monocyte-replenishment rate currently attributed to gut macrophages. Moreover, all macrophage subpopulations required live microbiota to sustain their numbers, not only those derived from blood monocytes. These findings oppose the prevailing paradigm that all macrophages in the adult mouse gut rapidly turn over from monocytes in a microbiome-dependent manner; instead, these findings supplant it with a model of ontogenetic diversity where locally maintained subsets coexist with rapidly replaced monocyte-derived populations.


Assuntos
Antígenos CD4/metabolismo , Intestinos/citologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Animais , Animais Recém-Nascidos , Intestinos/microbiologia , Camundongos Endogâmicos C57BL , Microbiota , Monócitos/metabolismo , Fenótipo , Receptores CCR2/metabolismo , Transcrição Gênica
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