Homeostasis and response of IL-17-producing γδ T cells in peripheral tissues

Os mais de 30 anos de investigação sobre as células T γδ desde a sua descoberta mostraram que elas não seguem várias das “regras” ou paradigmas dos linfócitos T ditos “convencionais”, nomeadamente as células CD4+ e CD8+ da linhagem T αβ. Parte da biologia não convencional das células T γδ reside em seu programa de desenvolvimento tímico, que difere drasticamente dos linfócitos T αβ; enquanto estes precisam passar por processos periféricos de ativação e diferenciação, as células T γδ saem do timo com um programa efetor completamente maduro e estável. Dessa forma, os linfócitos T γδ chegam aos diferentes órgãos periféricos onde residem e exibem a sua capacidade de produzir citocinas pró-inflamatórias, nomeadamente IFN-γ ou IL-17 (estas últimas chamadas linfócitos T γδ17). Esse programa de desenvolvimento pouco flexível contrasta com evidências recentes que atribuem características adaptativas às respostas de células T γδ, e sugerem um papel central para essas células na detecção e integração de sinais ambientais. As células T γδ17, em particular, são críticas no controle das respostas de outras populações do sistema imunológico e de diferentes comunidades microbianas comensais, em diferentes tecidos de mucosa; a geração dessas células, no entanto, é altamente dependente do período de maturação no timo, e acredita-se que sua geração seja limitada a um curto período do desenvolvimento embrionário. Portanto, na presente tese, procuramos determinar se precursores encontrados na medula óssea adulta são capazes de originar células T γδ17 em resposta a fatores encontrados no ambiente extra-tímico. Mostrámos que, de fato, as células T γδ17 podem ser geradas de novo em linfonodos periféricos em resposta a estímulos inatos. Através do uso de abordagens in vitro e in vivo, conseguimos identificar a citocina IL-23 como o principal regulador desse processo. Por fim, descobrimos que as células T γδ17 induzidas na periferia representam uma fração substancial do total de linfócitos T γδ produtores de IL-17 durante o curso da encefalomielite autoimune experimental, modelo animal da esclerose múltipla, destacando a importância biomédica dessas descobertas. Além de estudar o papel de fatores provenientes de tecidos periféricos na homeostase das células T γδ17, outro objetivo importante desta tese foi estabelecer os mecanismos pelos quais as células T γδ regulam a homeostase do sistema imune nos tecidos de mucosa, concentrando-se nos pulmões. Curiosamente, descobrimos que, embora murganhos deficientes em células T γδ tenham uma distribuição normal de células inatas e adaptativas no tecido pulmonar ao longo do desenvolvimento, animais nascidos de mães deficientes em células T γδ um viés na produção de citocinas do tipo 2 no pulmão logo após o nascimento. Tais efeitos parecem ser independentes da transferência de anticorpos maternos. Contudo, em concordância com diferenças encontradas na microbiota tanto das mães quanto de suas proles, o uso de um coquetel de antibióticos anula essas diferenças; sugerindo que a seleção de comunidades microbianas por células T γδ maternas é importante no estabelecimento da colonização microbiana da prole durante os primeiros dias de vida e, consequentemente, no desenvolvimento do sistema imunológico pulmonar. Em conjunto, os resultados obtidos nesta tese lançam nova luz sobre o processo de geração periférica de células T γδ17 no contexto de doenças inflamatórias. Além disso, revelam uma contribuição inesperada das células T γδ maternas no desenvolvimento do sistema imunológico pulmonar das suas crias, abrindo uma nova avenida na investigação do papel das células T γδ na imunidade nos tecidos de mucosa.The over 30 years of research on γδ T cells since their discovery have shown that they do not follow various “rules” or paradigms of the so-called conventional T cells, namely CD4+ and CD8+ αβ T cells. Part of the unconventional biology of γδ T cell resides in their thymic developmental program, which markedly differs from their ab counterparts. Whereas the latter need to go through peripheral processes of activation and differentiation, the former exit the thymus with fully mature effector programs. Thus, γδ T lymphocytes populate peripheral tissues as IFN-γ-producing or IL-17-producing γδ (γδ17) T cells, with limited functional plasticity. Such strict “developmental pre-programming” contrasts with recent evidences attributing adaptive features to γδ T cell responses, and suggestive of a central role for these cells in sensing and integrating environmental cues. γδ17 T cells, particularly, can be found in almost all barrier tissues in the body, being critical for the control of host immune responses and commensal microbial communities; these cells, however, seem to be highly dependent on thymic preprogramming, and their generation is thought to be constrained to a tight period during embryonic development. Therefore, in the present thesis we aimed to determine if adult bone marrow precursors are able to give rise to bona fide γδ17 T cells in response to environmental triggers outside the thymus. Here we found that γδ17 T cells can be generated de novo in draining lymph nodes in response to innate stimuli. By using both in vitro and in vivo approaches we were able to identify IL-23 as the major regulator of this process. Finally, we found that peripherally-induced γδ17 T cells represent a substantial fraction of total IL-17-producing γδ T cells during the course of experimental autoimmune encephalomyelitis, the mouse model for multiple sclerosis, highlighting the biomedical relevance of this novel pathway. In addition to studying the role of environmental cues in γδ17 T cell homeostasis, another major aim of this thesis was to establish the mechanisms by which γδ T cells regulate the homeostasis of the immune system at barrier tissues, focusing on the lungs. Interestingly, we found that although mice deficient in γδ T cells have a normal distribution of adaptive and innate cells throughout pulmonary development, the offspring of γδ T cell-deficient dams display a discrete pulmonary milieu early after birth, with a strong bias towards type-2 immune responses. Theses differences appear to be independent of maternal antibodies transfer. However, in line with differences in microbiota composition both in mothers and offspring, treatment with an antibiotic cocktail abrogates the differences observed in the cytokine milieu in the neonatal lungs of pups born from γδ T cell-deficient and -sufficient dams. Thus, suggesting that selection of microbial communities by maternal γδ T cells is critical in the initial microbial colonization of the offspring, and, as a consequence, in the development of a functional barrier immune system. Altogether, the results obtained in this thesis shed new light on the process of peripheral generation of γδ17 T cells in the context of inflammation, helping to change a dogma in the field. Additionally, by revealing a unanticipated role of maternal γδ T cells in the development of the immune system of the offspring, it opens a new research avenue on the role of γδ T cells at barrier tissues

Got my γδ17 T cells to keep me warm

© 2018 Nature America Inc., part of Springer Nature. All rights reservedγδ T cells accumulate with age in adipose tissue and produce the cytokine IL-17, which controls the homeostasis of regulatory T cells and adaptive thermogenesis. Thus, maintenance of core body temperature unexpectedly relies on these adipose tissue–resident γδ17 T cells.info:eu-repo/semantics/publishedVersio

Maternal γδ T cells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner.

Immune development is profoundly influenced by vertically transferred cues. However, little is known about how maternal innate-like lymphocytes regulate offspring immunity. Here, we show that mice born from γδ T cell-deficient (TCRδ-/-) dams display an increase in first-breath-induced inflammation, with a pulmonary milieu selectively enriched in type 2 cytokines and type 2-polarized immune cells, when compared with the progeny of γδ T cell-sufficient dams. Upon helminth infection, mice born from TCRδ-/- dams sustain an increased type 2 inflammatory response. This is independent of the genotype of the pups. Instead, the offspring of TCRδ-/- dams harbors a distinct intestinal microbiota, acquired during birth and fostering, and decreased levels of intestinal short-chain fatty acids (SCFAs), such as pentanoate and hexanoate. Importantly, exogenous SCFA supplementation inhibits type 2 innate lymphoid cell function and suppresses first-breath- and infection-induced inflammation. Taken together, our findings unravel a maternal γδ T cell-microbiota-SCFA axis regulating neonatal lung immunity

Crosstalk between γδ T cells and the microbiota.

From PubMed via Jisc Publications RouterHistory: received 2021-01-20, accepted 2021-07-07Publication status: aheadofprintFunder: European Molecular Biology Organization (EMBO); Grant(s): LTF 191-2019Funder: "la Caixa" Foundation (Caixa Foundation); Grant(s): LCF/PR/HR19/52160011Funder: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation); Grant(s): PZ00P3_185880The role of the microbiota in the development and function of γδ T cells-a T cell subset characterized by a T cell receptor composed of one γ-chain and one δ-chain-has been investigated in multiple organs in mice and humans. Interactions between the microbiota and γδ T cells affect both tissue homeostasis and disease pathologies. Notably, microbiota-induced interleukin-17 (IL-17)-producing-γδ T cells can mediate a range of immunological processes, from metabolic disorders to neuroinflammation via the gut-brain axis. However, the bidirectional interactions between γδ T cells and the microbiota have not been fully determined. In this Perspective, we dissect the roles of microbiota in modulating γδ T cell development and function, and evaluate the evidence for γδ T cell selection of commensal communities. We also discuss the potential implications of these cells in health and disease and the major open questions and research avenues in the field. [Abstract copyright: © 2021. Springer Nature Limited.

IL-17+ γδ T cells as kick-starters of inflammation

Copyright © 2017, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.Shortly after the discovery of interleukin 17 (IL-17)-producing CD4+ helper T cells (TH17 cells), it was found that γδ T cells can also secrete large amounts of this pro-inflammatory cytokine. A decade later, it is now known that IL-17+ γδ T cells (γδ17 T cells) are often the main providers of IL-17A in various models of inflammatory diseases, while they also contribute to protective immune responses to infectious organisms. Due to an intricate thymic program of differentiation, γδ17 T cells are able to respond faster than TH17 cells do and thus predominate in the early stages of inflammatory responses. Here we review the current knowledge of the development, activation and pathophysiological functions of γδ17 T cells, aiming to increase the awareness in the community of the therapeutic potential of this 'other side' of IL-17-mediated immune responses.Supported by the European Research Council (CoG_646701 to B.S.-S.) and Fundação para a Ciência e Tecnologia (PD/BD/105855/2014 to P.H.P.; IF/00013/2014 to J.C.R.).info:eu-repo/semantics/publishedVersio

MicroRNA-146a controls IFN-g production and functional plasticity of murine gd T cells by targeting Nod1

γδ T cells have emerged as key providers of the proinflammatory cytokines interleukin 17 (IL-17) and interferon-γ (IFN-γ) in various models of infection, inflammation, and autoimmunity. Our previous epigenetic and transcriptional analyses have shown that whereas CD27+ γδ T cells are committed to IFN-γ expression, the IL-17 producing CD27- subset has limited plasticity to co-express both cytokines under inflammatory conditions (Schmolka et al. Nat Immunol 2013). To further understand the molecular control of this plasticity we now investigated the potential role of microRNA (miRNA)-mediated post-transcriptional regulation.info:eu-repo/semantics/publishedVersio

The IL-17A-neutrophil axis promotes epithelial cell IL-33 production during nematode lung migration

The early migratory phase of pulmonary helminth infections is characterized by tissue injury leading to the release of the alarmin IL-33 and subsequent induction of type 2 immune responses. We recently described a role for IL-17A, through suppression of IFNγ, as an important inducer of type 2 responses during infection with the lung-migrating rodent nematode Nippostrongylus brasiliensis. Here, we aimed to investigate the interaction between IL-17A and IL-33 during the early lung migratory stages of N. brasiliensis infection. In this brief report, we demonstrate that deficiency of IL-17A leads to impaired IL-33 expression and secretion early in infection, independent of IL-17A suppression of IFNγ. Neutrophil-depletion experiments, which dramatically reduce lung injury, revealed that neutrophils are primarily responsible for the IL-17A-dependent release of IL-33 into the airways. Taken together, our results reveal an IL-17A-neutrophil-axis that can drive IL-33 during helminth infection, highlighting an additional pathway by which IL-17A regulates pulmonary type 2 immunity.</p

MicroRNA-146a controls functional plasticity in γδ T cells by targeting NOD1

γδ T cells are major providers of proinflammatory cytokines. They are preprogrammed in the mouse thymus into distinct subsets producing either interleukin-17 (IL-17) or interferon-γ (IFN-γ), which segregate with CD27 expression. In the periphery, CD27- γδ (γδ27-) T cells can be induced under inflammatory conditions to coexpress IL-17 and IFN-γ; the molecular basis of this functional plasticity remains to be determined. On the basis of differential microRNA (miRNA) expression analysis and modulation in γδ T cell subsets, we identified miR-146a as a thymically imprinted post-transcriptional brake to limit IFN-γ expression in γδ27- T cells in vitro and in vivo. On the basis of biochemical purification of Argonaute 2-bound miR-146a targets, we identified Nod1 to be a relevant mRNA target that regulates γδ T cell plasticity. In line with this, Nod1-deficient mice lacked multifunctional IL-17+ IFN-γ+ γδ27- cells and were more susceptible to Listeria monocytogenes infection. Our studies establish the miR-146a/NOD1 axis as a key determinant of γδ T cell effector functions and plasticity.info:eu-repo/semantics/publishedVersio