Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells

Abstract

Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8α+ conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3−/− mice also lack CD103+CD11b− DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3−/− mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103+CD11b− DCs, with the population of CD103+CD11b+ DCs remaining intact. Batf3−/− mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103+ DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8α+ cDCs and nonlymphoid CD103+ DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ–resident CD8α+ cDCs and nonlymphoid CD103+ DCs.

Identification of Teleost Skin CD8α+ Dendritic-like Cells, Representing a Potential Common Ancestor for Mammalian Cross-Presenting Dendritic Cells

“…These findings support the hypothesis that mammalian cross-presenting DCs, including murine lymphoid CD8 + DCs, murine tissue CD103 + DCs, and the human CD141 lineage, share a common ancestor that has been conserved through evolution in teleost fish. Previous evidence that led other investigators to formulate the hypothesis includes the expression of common transcription factors, such as Batf3 (20,21) and IRF8 (18,19), the sensitivity to TLR3 ligands, and the use of CLEC9A and XCR1 (18,19,(22)(23)(24)29). We were able to identify CLEC9A and XCR1 homologs in trout EST databases, but we showed that the skin CD8 + DC-like subpopulation expressed both Batf3 and IRF8, distinctive transcription factors essential in the development of cross-presenting DCs.…”

“…Recent data suggest that, in mice, both of these cross-presenting DCs, lymphoid CD8a + DCs and tissue-derived CD103 + DCs, form a common DC lineage. The functionality of these two DC subtypes is dependent on similar transcription factors (17), and they are derived exclusively from pre-DCs under the control of Flt3 ligand, IFN regulatory protein (IRF)8 (18,19), and Batf3 (20,21). Additionally, both populations use the CLEC9A lectin to recognize necrotic cells (22) and express the chemokine receptor XCR1 (23).…”

Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation

“…38 Series of our studies have shown that pDCablated mice exhibited a near-complete and specific elimination of pDCs in the lymphoid tissues following DT treatment, but they retained other leukocytes, including cDC subsets. 31,32 Analysis of pDC-ablated mice revealed that the development of DSS-induced acute colitis was attenuated in the absence of pDCs.…”

Transcription factor networks in dendritic cell development

“…Mice deficient in Batf3 have normal numbers of precursors, including CDPs and pre-cDCs [85], and appear deficient in only the most terminal stage of CD8 + DC maturation. This final step is defined by the induction of genes important for the function of this DC subset, including Langerin and CD103.…”