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1.
Mucosal Immunol ; 16(6): 767-775, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37783278

RESUMO

The early migratory phase of pulmonary helminth infections is characterized by tissue injury leading to the release of the alarmin interleukin (IL)-33 and subsequent induction of type 2 immune responses. We recently described a role for IL-17A, through suppression of interferon (IFN)-γ, 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 IFN-γ. 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.


Assuntos
Nematoides , Neutrófilos , Animais , Camundongos , Interleucina-17/metabolismo , Interleucina-33 , Pulmão , Células Epiteliais/metabolismo , Camundongos Endogâmicos C57BL
2.
Cell Rep ; 42(2): 112074, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36787741

RESUMO

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.


Assuntos
Microbioma Gastrointestinal , Imunidade Inata , Animais , Camundongos , Linfócitos , Inflamação , Pulmão , Camundongos Endogâmicos C57BL
3.
Nat Microbiol ; 6(9): 1110-1117, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34341528

RESUMO

The 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.


Assuntos
Microbioma Gastrointestinal , Subpopulações de Linfócitos T/imunologia , Animais , Encéfalo/imunologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Neuroimunomodulação , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia
4.
Sci Immunol ; 3(23)2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29728425

RESUMO

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.


Assuntos
MicroRNAs/imunologia , Proteína Adaptadora de Sinalização NOD1/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Proteínas de Ligação a DNA/genética , Listeria monocytogenes , Listeriose/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Proteína Adaptadora de Sinalização NOD1/genética
6.
J Autoimmun ; 87: 26-37, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29203226

RESUMO

IL-17-producing γδ (γδ17) T cells form a versatile subset of cells that respond rapidly to innate stimuli and support the pro-inflammatory functions of different myeloid and lymphoid lineages, being particularly critical in the early stages of inflammatory and autoimmune responses. In mice, under homeostatic conditions, these innate-like lymphocytes are pre-programmed in the fetal thymus, through an intricate process involving both T cell receptor-dependent and -independent signals, which allows them to readily produce IL-17 upon stimulation. However, given their transcriptional and epigenetic wiring, γδ17 T cells are permissive to different environmental instructions, and can readily acquire the ability to co-produce multiple cytokines, such as IFN-γ, IL-22 and GM-CSF, that further propagate inflammation. Moreover, strong IL-23 signals, which are abundantly found in autoinflammatory conditions, are able to induce de novo differentiation of γδ17 T cells from uncommitted precursors, both in mice and humans. This notwithstanding, the exact mechanisms responsible for γδ17 T cell pathogenicity and multifunctionality are still poorly understood, especially in humans. The pathogenic roles attributed to γδ17 T cells in autoimmune diseases stem mainly from their ability to recruit different inflammatory myeloid populations to the target tissue, and to modulate αß T cell function, either by enhancing inflammatory TH17 responses, or by restraining regulatory Treg cell activity. Given their capacity to link key inflammatory axes of innate and adaptive immunity, a better understanding of the molecular basis underpinning γδ17 T cell plasticity, and how much this feature accounts for their pathophysiological roles, may be critical for developing novel therapeutic approaches. In this review, we discuss the importance of γδ17 T cells in breaking tolerance and enhancing inflammation in various autoimmune diseases, such as multiple sclerosis, psoriasis and rheumatoid arthritis under the light of their basic biological traits, e.g. development, activation, effector functions and plasticity.


Assuntos
Doenças Autoimunes/imunologia , Inflamação/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T/imunologia , Células Th17/imunologia , Animais , Comunicação Celular , Diferenciação Celular , Plasticidade Celular , Humanos , Tolerância Imunológica , Imunidade Inata , Interleucina-17/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
7.
EMBO Rep ; 18(11): 1957-1967, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28855306

RESUMO

Pro-inflammatory interleukin (IL)-17-producing γδ (γδ17) T cells are thought to develop exclusively in the thymus during fetal/perinatal life, as adult bone marrow precursors fail to generate γδ17 T cells under homeostatic conditions. Here, we employ a model of experimental autoimmune encephalomyelitis (EAE) in which hematopoiesis is reset by bone marrow transplantation and demonstrate unequivocally that Vγ4+ γδ17 T cells can develop de novo in draining lymph nodes in response to innate stimuli. In vitro, γδ T cells from IL-17 fate-mapping reporter mice that had never activated the Il17 locus acquire IL-17 expression upon stimulation with IL-1ß and IL-23. Furthermore, IL-23R (but not IL-1R1) deficiency severely compromises the induction of γδ17 T cells in EAE, demonstrating the key role of IL-23 in the process. Finally, we show, in a composite model involving transfers of both adult bone marrow and neonatal thymocytes, that induced γδ17 T cells make up a substantial fraction of the total IL-17-producing Vγ4+ T-cell pool upon inflammation, which attests the relevance of this novel pathway of peripheral γδ17 T-cell differentiation.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interleucina-23/imunologia , Linfonodos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Células Th17/imunologia , Animais , Medula Óssea/imunologia , Medula Óssea/patologia , Transplante de Medula Óssea , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/imunologia , Movimento Celular , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Hematopoese/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-1beta/farmacologia , Interleucina-23/genética , Interleucina-23/farmacologia , Linfonodos/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Transdução de Sinais , Células Th17/patologia , Timo/imunologia , Timo/patologia
8.
Nat Immunol ; 18(6): 604-611, 2017 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-28518154

RESUMO

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.


Assuntos
Inflamação/imunologia , Interleucina-17/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular/imunologia , Humanos , Imunidade Inata/imunologia , Camundongos , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Timo , Recombinação V(D)J
9.
Antibodies (Basel) ; 6(4)2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31548534

RESUMO

The effector functions of T lymphocytes are responsible for most autoimmune disorders and act by directly damaging tissues or by indirectly promoting inflammation and antibody responses. Co-stimulatory and co-inhibitory T cell receptor molecules are the primary pharmacological targets that enable interference with immune-mediated diseases. Among these, selective CD28 antagonists have drawn special interest, since they tip the co-stimulation/co-inhibition balance towards efficiently inhibiting effector T cells while promoting suppression by pre-existing regulatory T-cells. After having demonstrated outstanding therapeutic efficacy in multiple models of autoimmunity, inflammation and transplantation, and safety in phase-I studies in humans, selective CD28 antagonists are currently in early clinical development for the treatment of systemic lupus erythematous and rheumatoid arthritis. Here, we review the available proof of concept studies for CD28 antagonists in autoimmunity, with a special focus on the mechanisms of action.

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