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Rapid activation of memory CD4(+) T helper 2 (TH2) cells during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid (ILC2) cells have a crucial role in memory TH2 cell responses, with targeted depletion of ILC2 cells profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin 13 (IL-13) is critical for eliciting production of the TH2 cell-attracting chemokine CCL17 by IRF4(+)CD11b(+)CD103(-) dendritic cells (DCs). Consequently, the sentinel function of DCs is contingent on ILC2 cells for the generation of an efficient memory TH2 cell response. These results elucidate a key innate mechanism in the regulation of the immune memory response to allergens.
Assuntos
Células Dendríticas/imunologia , Hipersensibilidade/imunologia , Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Células Th2/imunologia , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.
Assuntos
Comunicação Celular/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Nippostrongylus/imunologia , Células Th2/imunologia , Animais , Apresentação de Antígeno/imunologia , Diferenciação Celular/imunologia , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Imunidade Celular , Imunidade Inata , Interleucina-13/biossíntese , Interleucina-13/metabolismo , Interleucina-2/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
The differentiation of several T- and B-cell effector programs in the immune system is directed by signature transcription factors that induce rapid epigenetic remodelling. Here we report that promyelocytic leukaemia zinc finger (PLZF), the BTB-zinc finger (BTB-ZF) transcription factor directing the innate-like effector program of natural killer T-cell thymocytes, is prominently associated with cullin 3 (CUL3), an E3 ubiquitin ligase previously shown to use BTB domain-containing proteins as adaptors for substrate binding. PLZF transports CUL3 to the nucleus, where the two proteins are associated within a chromatin-modifying complex. Furthermore, PLZF expression results in selective ubiquitination changes of several components of this complex. CUL3 was also found associated with the BTB-ZF transcription factor BCL6, which directs the germinal-centre B cell and follicular T-helper cell programs. Conditional CUL3 deletion in mice demonstrated an essential role for CUL3 in the development of PLZF- and BCL6-dependent lineages. We conclude that distinct lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the ubiquitination pattern of their associated chromatin-modifying complex. We propose that this new function is essential to direct the differentiation of several T- and B-cell effector programs, and may also be involved in the oncogenic role of PLZF and BCL6 in leukaemias and lymphomas.
Assuntos
Linfócitos B/metabolismo , Proteínas Culina/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Linfócitos T/metabolismo , Dedos de Zinco , Animais , Linfócitos B/citologia , Diferenciação Celular , Linhagem Celular , Proteínas Culina/química , Proteínas Culina/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos , Proteína com Dedos de Zinco da Leucemia Promielocítica , Ligação Proteica , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-6 , Linfócitos T/citologia , UbiquitinaçãoRESUMO
Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.
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Highlights from the Science family of journals.