Derivation of 2 categories of plasmacytoid dendritic cells in murine bone marrow

Abstract

Plasmacytoid dendritic cells (pDCs) competent to make type I interferon were rigorously defined as a Ly-6C ؉ and CD11c Lo subset of the B220 ؉ CD19 ؊ CD43 ؉ CD24 Lo bone marrow (BM) Fraction A. Otherwise similar Ly6C ؊ cells expressed the natural killer (NK) markers DX5 and NK1.1. pDCs represented a stable, discrete, and long-lived population. Stem cells and early lymphoid progenitors (ELPs), but not prolymphocytes, were effective precursors of pDCs, and their differentiation was blocked by ligation of Notch receptors. Furthermore, pDCs were present in the BM of RAG1 ؊/؊ , CD127/IL-7Ra ؊/؊ , and Pax5 ؊/؊ mice. pDCs in RAG1/GFP knock-in mice could be subdivided, and immunoglobulin D H -J H rearrangements, as well as transcripts for the B-lineagerelated genes Pax5, mb1/CD79a, ebf, and Bcl11a, were identified only in the green fluorescent protein-positive (GFP ؉ ) pDC1 subset. All pDCs expressed terminal deoxynucleotidyl transferase (TdT), the ETS transcription factor Spi-B, the nuclear factor-B transcription factor RelB, toll-like receptor 9 (TLR9), and interferon consensus sequence binding protein (ICSBP)/interferon regulatory factor 8 (IRF-8) transcripts; lacked CD16 and granulocyte colony-stimulating factor receptor (G-CSFR); and were uniformly interleukin-7 receptor ␣ (IL-7R␣ ؊ ) AA4.1 Lo , CD27 ؊ , Flk-2 Lo , c-Kit ؊ , DX-5 ؊ , and CD11b ؊ , while CD4 and CD8␣ were variable. GFP ؉ pDC1 subset was less potent than GFP ؊ pDC2s in T allostimulation and production of tumor necrosis factor ␣ (TNF␣), interferon ␣ (IFN␣), and interleukin-6 (IL-6), while only pDC2s made IFN␥ and IL-12 p70. Thus, 2 functionally specialized subsets of pDCs arise in bone marrow from progenitors that diverge from B, T, and NK lineages at an early stage. IntroductionPlasmacytoid dendritic cells (pDCs) are believed to play central roles in defense of viral infection and maintenance of T-cell tolerance. They represent a principal source of type I interferon and can produce inflammatory cytokines such as interleukin-12 (IL-12) p70, IL-6, and tumor necrosis factor ␣ (TNF␣). 1,2 Furthermore, pDCs have been implicated in the pathogenesis of lupus in humans. [3][4][5] While information is rapidly accumulating about pDCs, important questions remain about their origin, heterogeneity, and lifespan. The focus of our study was on pDCs that reside within bone marrow (BM).CD11c Ϫ CD123 Hi HLA class II Hi BDCA (blood dendritic cell antigen) ϩ pDCs were originally defined in human blood and distinguished from conventional CD11c ϩ CD123 Ϫ dendritic cells (DCs). [6][7][8][9] The murine counterparts of human pDCs express CD11c and CD45R/B220, but not CD19, 10,11 while murine DCs as a whole can be divided into CD8 Ϫ and CD8 ϩ subpopulations. 12 Although distinct from classical murine CD8 ϩ DCs, pDCs express variable levels of CD8. 1,13,14 They were formerly defined as CD11c Lo B220 ϩ Gr1 ϩ in spleen and as CD11c ϩ B220 ϩ CD11b Ϫ cells when derived from BM cultured with FMS-like tyrosine kinase 3 ligand (Flt3-L). 15 Expression of Ly6G/Gr1 on pDCs is controve...

The network of cytokines, receptors and transcription factors governing the development of dendritic cell subsets

“…Recently, with the description of CDP, pDC have been assumed to have a myeloid origin. While other studies have suggested pDC differentiate via both lymphoid and myeloid routes (Corcoran et al, 2003;D'Amico and Wu, 2003;Shigematsu et al, 2004;Pelayo et al, 2005). These conclusions are yet to be confirmed in vivo.…”

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

“…Selective Tcf4 gene ablation in IDO-competent cells and B cells from mice harboring a Cd23-Cre transgene confirmed that both cell types develop from immature B-cell progenitors (22). Cells with classic features of B cells and DCs can develop from B-cell progenitors (34). Plasmablasts in splenic extrafollicular regions that promote T-independent humoral responses also expressed CD11c, albeit at lower levels than IDO-competent cells (35).…”

The BCL11AXL transcription factor: its distribution in normal and malignant tissues and use as a marker for plasmacytoid dendritic cells

“…Additional support for BCL11A expression in this subset of dendritic cells is provided by the recent report of Bcl11a transcripts in murine pDCs. 4 Nuclear labeling for BCL11A XL was observed in a subpopulation of cells in thymus. Although the majority of the medullary BCL11A XL -positive cells were CD20-positive B cells, scattered CD20-negative cells with strongly stained nuclei, reminiscent of the pDCs described above, were also observed ( Figure 1j).…”