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/patologiaRESUMO
Innate lymphoid cells (ILCs) are tissue-resident effector cells with roles in tissue homeostasis, protective immunity, and inflammatory disease. Group 3 ILCs (ILC3s) are classically defined by the master transcription factor RORγt. However, ILC3 can be further subdivided into subsets that share type 3 effector modules that exhibit significant ontological, transcriptional, phenotypic, and functional heterogeneity. Notably lymphoid tissue inducer (LTi)-like ILC3s mediate effector functions not typically associated with other RORγt-expressing lymphocytes, suggesting that additional transcription factors contribute to dictate ILC3 subset phenotypes. Here, we identify Bcl6 as a subset-defining transcription factor of LTi-like ILC3s in mice and humans. Deletion of Bcl6 results in dysregulation of the LTi-like ILC3 transcriptional program and markedly enhances expression of interleukin-17A (IL-17A) and IL-17F in LTi-like ILC3s in a manner in part dependent upon the commensal microbiota-and associated with worsened inflammation in a model of colitis. Together, these findings redefine our understanding of ILC3 subset biology.
Assuntos
Linfócitos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Animais , Humanos , Camundongos , Imunidade Inata , Linfócitos/metabolismo , Tecido Linfoide/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Group 3 innate lymphoid cells (ILC3) are potent effector cells with critical roles in enforcing immunity, barrier integrity and tissue homeostasis along the gastrointestinal tract. ILC3 are considered primarily tissue-resident cells, seeding the gastrointestinal tract during embryonic stages and early life. However, the mechanisms through which mature ILC3 are maintained within adult tissues are poorly understood. Here, we report that lymphoid tissue-inducer-like (LTi-like) ILC3 exhibit minimal turnover in the healthy adult intestinal tract, persist for extended periods of time, and display a quiescent phenotype. Strikingly, during enteric bacterial infection LTi-like ILC3 also exhibit negligible hematopoietic replenishment and remain non-proliferative, despite robustly producing cytokines. Survival of LTi-like ILC3 was found to be dependent upon the balance between the metabolic activity required to drive effector function and anti-apoptotic programs. Notably, the pro-survival protein B-cell lymphoma-2 (Bcl-2) was required for the survival of LTi-like ILC3 ex vivo but was rendered partially dispensable if mitochondrial respiration was inhibited. Together we demonstrate LTi-like ILC3 are a tissue-resident, quiescent population that persist independently of hematopoietic replenishment to survive within the intestinal microenvironment.
Assuntos
Imunidade Inata , Linfócitos , Tecido Linfoide/metabolismo , Citocinas/metabolismo , FenótipoRESUMO
Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens-including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 are found to be uniquely preprimed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine-producing capacity of ILC2. Mechanistically, amino acid uptake determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.
Assuntos
Imunidade Inata , Linfócitos , Linfócitos/metabolismo , Aminoácidos/metabolismo , Citocinas/metabolismo , Mucosa/metabolismoRESUMO
Recently, there has been a growing interest in deploying smart materials as sensing components of structural health monitoring systems. In this arena, piezoelectric materials offer great promise for researchers to rapidly expand their many potential applications. The main goal of this study is to review the state-of-the-art piezoelectric-based sensing techniques that are currently used in the structural health monitoring area. These techniques range from piezoelectric electromechanical impedance and ultrasonic Lamb wave methods to a class of cutting-edge self-powered sensing systems. We present the principle of the piezoelectric effect and the underlying mechanisms used by the piezoelectric sensing methods to detect the structural response. Furthermore, the pros and cons of the current methodologies are discussed. In the end, we envision a role of the piezoelectric-based techniques in developing the next-generation self-monitoring and self-powering health monitoring systems.