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/metabolismoRESUMO
Infection with helminths can protect against the development of autoimmune diseases and this has been associated with induction of anti-inflammatory innate immune responses and Tregs. Here, we demonstrate that helminth-derived products can directly target T cells, especially IL-17-secreting γδ T cells that play a key pathogenic role in CNS autoimmune disease.
Assuntos
Encefalomielite Autoimune Experimental/terapia , Fasciola hepatica/imunologia , Fasciolíase/imunologia , Esclerose Múltipla/terapia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Terapia com Helmintos/métodos , Animais , Antígenos de Helmintos/imunologia , Extratos Celulares/imunologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Terapia de Imunossupressão , Camundongos , Glicoproteína Mielina-Oligodendrócito/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismoRESUMO
Regulatory T (Treg) cells help to maintain tolerance and prevent the development of autoimmune diseases. Retinoic acid (RA) can promote peripheral conversion of naïve T cells into Foxp3+ Treg cells. Here, we show that RA can act as an adjuvant to induce antigen-specific type 1 Treg (Tr1) cells, which is augmented by co-administration of IL-2. Immunization of mice with the model antigen KLH in the presence of RA and IL-2 induces T cells that secrete IL-10, but not IL-17 or IFN-γ, and express LAG-3, CD49b and PD-1 but not Foxp3, a phenotype typical of Tr1 cells. Furthermore, immunization of mice with the autoantigen MOG in the presence of RA and IL-2 induces Tr1 cells, which suppress pathogenic Th1 and Th17 cells that mediate the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS. Furthermore, immunization with a surrogate autoantigen, RA and IL-2 prevents development of spontaneous autoimmune uveitis. Our findings demonstrate that the induction of autoantigen-specific Tr1 cells can prevent the development of autoimmunity.
Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Linfócitos T Reguladores/imunologia , Tretinoína/imunologia , Animais , Encefalomielite Autoimune Experimental/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th17/imunologiaRESUMO
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 Th17â¯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 (Th17â¯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 Th17â¯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 Th17â¯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 Th17â¯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.