RESUMO
Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4. T cell-specificPros1knockouts phenocopied the loss ofTyro3 Thus, a PROS1-mediated feedback from adaptive immunity engages a rheostat, TYRO3, on innate immune cells to limit the intensity of type 2 responses.
Assuntos
Imunidade Adaptativa/genética , Asma/imunologia , Interações Hospedeiro-Parasita/imunologia , Imunidade Inata/genética , Receptores Proteína Tirosina Quinases/fisiologia , Animais , Asma/genética , Proteínas Sanguíneas/antagonistas & inibidores , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Células Dendríticas/imunologia , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Interações Hospedeiro-Parasita/genética , Humanos , Interleucina-4/imunologia , Interleucina-4/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nippostrongylus/imunologia , Proteína S , Pyroglyphidae/imunologia , Receptores Proteína Tirosina Quinases/genética , Infecções por Strongylida/imunologia , Linfócitos T/imunologiaRESUMO
Exposure to a plethora of environmental challenges commonly triggers pathological type 2 cell-mediated inflammation. Here we report the pathological role of the Wnt antagonist Dickkopf-1 (Dkk-1) upon allergen challenge or non-healing parasitic infection. The increased circulating amounts of Dkk-1 polarized T cells to T helper 2 (Th2) cells, stimulating a marked simultaneous induction of the transcription factors c-Maf and Gata-3, mediated by the kinases p38 MAPK and SGK-1, resulting in Th2 cell cytokine production. Circulating Dkk-1 was primarily from platelets, and the increase of Dkk-1 resulted in formation of leukocyte-platelet aggregates (LPA) that facilitated leukocyte infiltration to the affected tissue. Functional inhibition of Dkk-1 impaired Th2 cell cytokine production and leukocyte infiltration, protecting mice from house dust mite (HDM)-induced asthma or Leishmania major infection. These results highlight that Dkk-1 from thrombocytes is an important regulator of leukocyte infiltration and polarization of immune responses in pathological type 2 cell-mediated inflammation.
Assuntos
Asma/imunologia , Plaquetas/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Leishmania major/imunologia , Leishmaniose Cutânea/imunologia , Células Th2/imunologia , Proteínas Wnt/antagonistas & inibidores , Animais , Antígenos de Dermatophagoides/imunologia , Antígenos de Protozoários/imunologia , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Animais , Pyroglyphidae , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Dendritic cell (DC) activation is essential for the induction of immune defense against pathogens, yet needs to be tightly controlled to avoid chronic inflammation and exaggerated immune responses. Here, we identify a mechanism of immune homeostasis by which adaptive immunity, once triggered, tempers DC activation and prevents overreactive immune responses. T cells, once activated, produced Protein S (Pros1) that signaled through TAM receptor tyrosine kinases in DCs to limit the magnitude of DC activation. Genetic ablation of Pros1 in mouse T cells led to increased expression of costimulatory molecules and cytokines in DCs and enhanced immune responses to T cell-dependent antigens, as well as increased colitis. Additionally, PROS1 was expressed in activated human T cells, and its ability to regulate DC activation was conserved. Our results identify a heretofore unrecognized, homeostatic negative feedback mechanism at the interface of adaptive and innate immunity that maintains the physiological magnitude of the immune response.