Mucosal Immunobiology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2013 Sep 1;191(5):2771-9. doi: 10.4049/jimmunol.1301093. Epub 2013 Aug 2.
We explored the function of endogenous type I IFNs (IFN-1) in the colon using the T cell adoptive transfer model of colitis. Colon mononuclear phagocytes (MPs) constitutively produced IFN-1 in a Toll/IL-1R domain-containing adapter-inducing IFN-β-dependent manner. Transfer of CD4(+)CD45RB(hi) T cells from wild-type (WT) or IFN-α/β receptor subunit 1 knockout (IFNAR1(-/-)) mice into RAG(-/-) hosts resulted in similar onset and severity of colitis. In contrast, RAG(-/-) × IFNAR1(-/-) double knockout (DKO) mice developed accelerated severe colitis compared with RAG(-/-) hosts when transferred with WT CD4(+)CD45RB(hi) T cells. IFNAR signaling on host hematopoietic cells was required to delay colitis development. MPs isolated from the colon lamina propria of IFNAR1(-/-) mice produced less IL-10, IL-1R antagonist, and IL-27 compared with WT MPs. Accelerated colitis development in DKO mice was characterized by early T cell proliferation and accumulation of CD11b(+)CD103(-) dendritic cells in the mesenteric lymph nodes, both of which could be reversed by systemic administration of IL-1R antagonist (anakinra). Cotransfer of CD4(+)CD25(+) regulatory T cells (Tregs) from WT or IFNAR1(-/-) mice prevented disease caused by CD4(+)CD45RB(hi) T cells. However, WT CD4(+)CD25(+)Foxp3(GFP+) Tregs cotransferred with CD4(+)CD45RB(hi) T cells into DKO hosts failed to expand or maintain Foxp3 expression and gained effector functions in the colon. To our knowledge, these data are the first to demonstrate an essential role for IFN-1 in the production of anti-inflammatory cytokines by gut MPs and the indirect maintenance of intestinal T cell homeostasis by both limiting effector T cell expansion and promoting Treg stability.
我们使用 T 细胞过继转移结肠炎模型来探索内源性 I 型干扰素（IFN-1）在结肠中的功能。结肠单核吞噬细胞（MPs）以 Toll/IL-1R 结构域包含衔接诱导 IFN-β 的方式组成性地产生 IFN-1。从野生型（WT）或 IFN-α/β 受体亚单位 1 敲除（IFNAR1(-/-)）小鼠过继转移 CD4(+)CD45RB(hi)T 细胞到 RAG(-/-)宿主中导致结肠炎的发生和严重程度相似。相比之下，当用 WT CD4(+)CD45RB(hi)T 细胞过继转移到 RAG(-/-)×IFNAR1(-/-)双敲除（DKO）小鼠中时，与 RAG(-/-)宿主相比，DKO 小鼠发展为加速严重的结肠炎。宿主造血细胞上的 IFNAR 信号传导是延迟结肠炎发展所必需的。与 WT MPs 相比，IFNAR1(-/-)小鼠结肠固有层分离的 MPs 产生的 IL-10、IL-1R 拮抗剂和 IL-27 较少。DKO 小鼠加速的结肠炎发展的特征是早期 T 细胞增殖和肠系膜淋巴结中 CD11b(+)CD103(-)树突状细胞的积累，这两者都可以通过全身给予 IL-1R 拮抗剂（anakinra）来逆转。从 WT 或 IFNAR1(-/-)小鼠过继转移 CD4(+)CD25(+)调节性 T 细胞（Tregs）可预防 CD4(+)CD45RB(hi)T 细胞引起的疾病。然而，WT CD4(+)CD25(+)Foxp3(GFP+)Tregs 与 CD4(+)CD45RB(hi)T 细胞一起过继转移到 DKO 宿主中未能扩增或维持 Foxp3 表达，并在结肠中获得效应功能。据我们所知，这些数据首次证明 IFN-1 在肠道 MPs 产生抗炎细胞因子中以及通过限制效应 T 细胞扩增和促进 Treg 稳定性间接维持肠道 T 细胞稳态方面发挥着重要作用。
