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1.
Immunity ; 52(2): 342-356.e6, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32023490

RESUMO

Interleukin-17A (IL-17A) is a major mediator of tissue inflammation in many autoimmune diseases. Anti-IL-17A is an effective treatment for psoriasis and is showing promise in clinical trials in multiple sclerosis. In this study, we find that IL-17A-defective mice or mice treated with anti-IL-17A at induction of experimental autoimmune encephalomyelitis (EAE) are resistant to disease and have defective priming of IL-17-secreting γδ T (γδT17) cells and Th17 cells. However, T cells from Il17a-/- mice induce EAE in wild-type mice following in vitro culture with autoantigen, IL-1ß, and IL-23. Furthermore, treatment with IL-1ß or IL-17A at induction of EAE restores disease in Il17a-/- mice. Importantly, mobilization of IL-1ß-producing neutrophils and inflammatory monocytes and activation of γδT17 cells is reduced in Il17a-/- mice. Our findings demonstrate that a key function of IL-17A in central nervous system (CNS) autoimmunity is to recruit IL-1ß-secreting myeloid cells that prime pathogenic γδT17 and Th17 cells.


Assuntos
Autoimunidade/imunologia , Interleucina-17/imunologia , Interleucina-1beta/metabolismo , Linfócitos Intraepiteliais/imunologia , Células Mieloides/imunologia , Células Th17/imunologia , Animais , Autoantígenos/imunologia , Autoimunidade/genética , Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/deficiência , Interleucina-17/metabolismo , Interleucina-1beta/imunologia , Interleucina-23/imunologia , Interleucina-23/metabolismo , Linfócitos Intraepiteliais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Células Mieloides/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Células Th17/metabolismo
2.
EMBO J ; 43(14): 2878-2907, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38816652

RESUMO

In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αß-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27+ Ly6C- cells convert into CD27+Ly6C+ cells, and these CD27+Ly6C+ cells control cancer progression in mice, while the CD27+Ly6C- cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human Vδ2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C- cell and human Vδ1+ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology.


Assuntos
Antígenos Ly , Receptores de Antígenos de Linfócitos T gama-delta , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral , Animais , Camundongos , Antígenos Ly/metabolismo , Antígenos Ly/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Humanos , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Interferon gama/metabolismo , Interferon gama/imunologia , Interleucina-27/metabolismo , Interleucina-27/genética , Diferenciação Celular/imunologia , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo
3.
Br J Cancer ; 124(1): 37-48, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262520

RESUMO

Major advances in cancer immunotherapy have dramatically expanded the potential to manipulate immune cells in cancer patients with metastatic disease to counteract cancer spread and extend patient lifespan. One of the most successful types of immunotherapy is the immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1, that keep anti-tumour T cells active. However, not every patient with metastatic disease benefits from this class of drugs and patients often develop resistance to these therapies over time. Tremendous research effort is now underway to uncover new immunotherapeutic targets that can be used in patients who are refractory to anti-CTLA-4 or anti-PD-1 treatment. Here, we discuss results from experimental model systems demonstrating that modulating the immune response can negatively affect metastasis formation. We focus on molecules that boost anti-tumour immune cells and opportunities to block immunosuppression, as well as cell-based therapies with enhanced tumour recognition properties for solid tumours. We also present a list of challenges in treating metastatic disease with immunotherapy that must be considered in order to move laboratory observations into clinical practice and maximise patient benefit.


Assuntos
Imunoterapia/métodos , Metástase Neoplásica/terapia , Neoplasias/patologia , Neoplasias/terapia , Animais , Humanos , Metástase Neoplásica/patologia
4.
J Autoimmun ; 2018 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-29395738

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) that shares many features with the human disease. This review will focus on the role of IL-17-secreting CD4 and γδ T cells in EAE and MS, the plasticity of Th17 cells in vivo and the application of these findings to the understating of the pathogenesis and the development of new treatments for MS. There is convincing evidence that IL-17-secreting CD4 T cells (Th17 cells) and IL-17-secreting γδ T cells play a critical pathogenic role in central nervous system (CNS) inflammation in EAE and MS. Indeed a significant number of the major discoveries on the pathogenic role of IL-17-secreting T cells in autoimmunity were made in the EAE model. These included the first demonstration that IL-23-activated IL-17-secreting T cells are the key T cells in driving autoimmune disease pathology. Although the early studies on IL-17 focused on Th17 cells, it was later demonstrated that γδ T cells were an important early source of IL-17 and IL-21 that helped amplify IL-17 production by Th17 cells in autoimmune diseases. Furthermore, it emerged that Th1 cells can also have encephalitogenic activity and that there was considerable plasticity in these T cell responses, with Th17 cells reverting to a Th1 phenotype in vivo. This questioned the pathogenic role of IL-17 and suggested that other cytokines, such as IFN-γ, GM-CSF and TNF, may be important. Nevertheless, biological drugs that target the IL-23-IL-17 pathway are highly effective in treating human psoriasis and are showing promise in the treatment of relapsing remitting MS and other T-cell mediated autoimmune diseases.

5.
Brain Behav Immun ; 50: 41-46, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26100487

RESUMO

Infection with viral or bacterial pathogens has been linked with the development of multiple sclerosis (MS), while infection with helminth parasites has been associated protection against MS and other autoimmune diseases. Here we have used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to examine the effect of infection with the respiratory pathogen Bordetella pertussis infection on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17(+), IFN-γ(+) and IFN-γ(+)IL-17(+) CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells in vitro and enhanced the frequency of IL-10-producing CD25(-)Foxp3(+/-) CD4(+) T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10(-/-) mice. Our findings demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS.


Assuntos
Bordetella pertussis/patogenicidade , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/microbiologia , Interleucina-10/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Animais , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th17/imunologia , Células Th17/microbiologia
6.
J Exp Med ; 220(2)2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-36480166

RESUMO

IL-17A-producing γδ T cells in mice consist primarily of Vγ6+ tissue-resident cells and Vγ4+ circulating cells. How these γδ T cell subsets are regulated during homeostasis and cancer remains poorly understood. Using single-cell RNA sequencing and flow cytommetry, we show that lung Vγ4+ and Vγ6+ cells from tumor-free and tumor-bearing mice express contrasting cell surface molecules as well as distinct co-inhibitory molecules, which function to suppress their expansion. Vγ6+ cells express constitutively high levels of PD-1, whereas Vγ4+ cells upregulate TIM-3 in response to tumor-derived IL-1ß and IL-23. Inhibition of either PD-1 or TIM-3 in mammary tumor-bearing mice increased Vγ6+ and Vγ4+ cell numbers, respectively. We found that genetic deletion of γδ T cells elicits responsiveness to anti-PD-1 and anti-TIM-3 immunotherapy in a mammary tumor model that is refractory to T cell checkpoint inhibitors, indicating that IL-17A-producing γδ T cells instigate resistance to immunotherapy. Together, these data demonstrate how lung IL-17A-producing γδ T cell subsets are differentially controlled by PD-1 and TIM-3 in steady-state and cancer.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A , Interleucina-17 , Neoplasias , Receptor de Morte Celular Programada 1 , Subpopulações de Linfócitos T , Animais , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo
7.
Discov Immunol ; 1(1): kyac002, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36277678

RESUMO

γδT cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance, homeostasis, and cancer. γδT cells recognize stressed cells or cancer cells through the NKG2D receptor to kill these cells and maintain normality. Contrary to the well-established anti-tumor function of these NKG2D-expressing γδT cells, we show here that, in mice, NKG2D regulates a population of pro-tumor γδT cells capable of producing IL-17A. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of γδT cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduced the capability of γδT cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increased the frequency of γδT cells. Together, these data support the hypothesis that, in a tumor microenvironment where NKG2D ligands are constitutively expressed, γδT cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A.

8.
J Exp Med ; 217(5)2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32106283

RESUMO

T cells are classically recognized as distinct subsets that express αß or γδ TCRs. We identify a novel population of T cells that coexpress αß and γδ TCRs in mice and humans. These hybrid αß-γδ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αß TCR-mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs. They expressed high levels of IL-1R1 and IL-23R and secreted IFN-γ, IL-17, and GM-CSF in response to canonically restricted peptide antigens or stimulation with IL-1ß and IL-23. Hybrid αß-γδ T cells were transcriptomically distinct from conventional γδ T cells and displayed a hyperinflammatory phenotype enriched for chemokine receptors and homing molecules that facilitate migration to sites of inflammation. These proinflammatory T cells promoted bacterial clearance after infection with Staphylococcus aureus and, by licensing encephalitogenic Th17 cells, played a key role in the development of autoimmune disease in the central nervous system.


Assuntos
Inflamação/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Animais , Biomarcadores/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Humanos , Inflamação/patologia , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Transcrição Gênica , Transcriptoma/genética
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