Varol Chen, Vallon-Eberhard Alexandra, Elinav Eran, Aychek Tegest, Shapira Yami, Luche Hervé, Fehling Hans Jörg, Hardt Wolf-Dietrich, Shakhar Guy, Jung Steffen
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel 76100.
Immunity. 2009 Sep 18;31(3):502-12. doi: 10.1016/j.immuni.2009.06.025. Epub 2009 Sep 3.
The intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. CD103(+) CX(3)CR1(-) lpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a Flt3L growth-factor-mediated pathway. CD11b(+) CD14(+) CX(3)CR1(+) lpDCs were derived from grafted Ly6C(hi) but not Ly6C(lo) monocytes under the control of GM-CSF. Mice reconstituted exclusively with CX(3)CR1(+) lpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-alpha-secreting CX(3)CR1(+) lpDCs. Our results highlight the critical importance of the lpDC subset balance for robust gut homeostasis.
肠道免疫系统能够区分对共生微生物群的耐受性和对病原体的强烈反应。这种关键平衡的维持归因于存在于有组织淋巴组织中并分散于上皮下固有层的黏膜树突状细胞（DC）。固有层DC（lpDC）的原位参数仍知之甚少。在此，我们结合条件性细胞消融和前体介导的体内重建，以确定lpDC亚群具有不同的起源和功能。CD103(+) CX(3)CR1(-) lpDC通过Flt3L生长因子介导的途径，从巨噬细胞-DC前体（MDP）经DC定向中间体（前cDC）产生。CD11b(+) CD14(+) CX(3)CR1(+) lpDC在GM-CSF的控制下，源自移植的Ly6C(hi)而非Ly6C(lo)单核细胞。在先天性结肠炎模型中受到挑战时，仅用CX(3)CR1(+) lpDC重建的小鼠会发生严重的肠道炎症，这是由移植来源的分泌TNF-α的CX(3)CR1(+) lpDC驱动的。我们的结果突出了lpDC亚群平衡对强大的肠道内环境稳定的至关重要性。
