Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions

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 (IpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that IpDC subsets have distinct origins and functions. CD103(+) CX(3)CR1(-) IpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a FIt3L growth-factor-mediated pathway. CD11b(+) CD14(+) hi CX(3)CR1(+) IpDCs were derived from grafted Ly6C(hi) but not Ly6C(lo) monocytes under the control of GMCSF. Mice reconstituted exclusively with CX(3)CR1(+) IpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-alpha-secreting CX(3)CR1(+) IpDCs. Our results highlight the critical importance of the IpDC subset balance for robust gut homeostasis.