Dendritic cell homeostasis

Abstract

Dendritic cells (DCs) are a heterogeneous fraction of rare hematopoietic cells that coevolved with the formation of the adaptive immune system. DCs efficiently process and present antigen, move from sites of antigen uptake to sites of cellular interactions, and are critical in the initiation of immune responses as well as in the maintenance of self-tolerance. DCs are distributed throughout the body and are enriched in lymphoid organs and environmental contact sites. Steady-state DC half-lives account for days to up to a few weeks, and they need to be replaced via proliferating hematopoietic progenitors, monocytes, or tissue resident cells. In this review, we integrate recent knowledge on DC progenitors, cytokines, and transcription factor usage to an emerging concept of in vivo DC homeostasis in steady-state and inflammatory conditions. We furthermore highlight how knowledge of these maintenance mechanisms might impact on understanding of DC malignancies as well as posttransplant immune reactions and their respective therapies.

Figure 1

Mouse DC populations, location, and turnover in steady state. DCs are distributed throughout the body. The major DC subpopulations at hematopoietic sites, environmental contact sites, filtering sites, and immune priming sites are depicted. Frequencies are given as percentage of total nucleated hematopoietic cells. Time to approximately 50% renewal in steady state is given in days (d). *Skin-draining LN; **epidermis; +present, but exact numbers not known; ↑, present in inflammation. Professional illustration by Debra T. Dartez.

Figure 2

DC migration and homeostasis. HSCs produce DC progenitors, pDCs, and DCs in the BM. Flt3 ligand is a nonredundant cytokine for BM DC differentiation, although the exact role of GM-CSF and M-CSFR ligands remains to be determined. BM-derived circulating blood cells maintain, with the exception of epidermal LCs, all known steady-state DC homeostasis in lymphoid and nonlymphoid tissues. We hypothesize that progenitor cells with limited proliferation potential on Flt3 ligand and LTβ stimulation enter the LNs through high endothelial venules to maintain the majority of LN DCs in steady state. It is also possible that nonproliferating blood DCs follow the same route. In addition, nonlymphoid tissue DCs continuously enter the LNs through afferent lymphatics, but these represent only a minority of steady-state LN DCs. The specific contribution of proliferating DC progenitors, blood DCs, and monocytes to nonlymphoid tissue DCs in the steady state and the relative involvement of cytokines as Flt3 ligand, GM-CSF, and M-CSFR ligands remain to be to be addressed. In contrast to most DCs, LCs repopulate locally in the steady state either through self-renewal or through a local hematopoietic precursor that takes residence in the skin. In inflamed skin, monocytes repopulate the LC pool via a TGF-β and monocyte colony-stimulating factor receptor–dependent pathway. In the steady state, pDCs are recruited to the LN and other lymphoid organs directly from the blood and, with the exception of the liver, enter most nonlymphoid tissues only on inflammation. Whether lymphoid organ pDCs also derive from DC precursors that enter the organs remains to be determined. *Likely, but not formally proven. Professional illustration by Debra T. Dartez.