Lymphoid precursors are directed to produce dendritic cells as a result of TLR9 ligation during herpes infection

Abstract

Hematopoietic stem and progenitor cells were previously found to express Tolllike receptors (TLRs), suggesting that bacterial/viral products may influence blood cell formation. We now show that common lymphoid progenitors (CLPs) from mice with active HSV-1 infection are biased to dendritic cell (DC) differentiation, and the phenomenon is largely TLR9 dependent. Similarly, CLPs from mice treated with the TLR9 ligand CpG ODN had little ability to generate CD19 ؉ B lineage cells and had augmented competence to generate DCs. TNF␣ mediates the depletion of late-stage lymphoid progenitors from bone marrow in many inflammatory conditions, but redirection of lymphopoiesis occurred in TNF␣ ؊/؊ mice treated with CpG ODN. Increased numbers of DCs with a lymphoid past were identified in Ig gene recombination substrate reporter mice treated with CpG ODN. TLR9 is highly expressed on lymphoid progenitors, and culture studies revealed that those receptors, rather than inflammatory cytokines, accounted for the production of several types of functional DCs. IntroductionHematopoietic stem cells (HSCs) give rise to progenitors with potential to produce blood cell types with remarkably stable characteristics. Although this process is tightly controlled, recent findings suggest that hematopoiesis is dynamic and also responsive to environmental factors. 1 The loss of differentiation options is gradual, and T lymphocytes, natural killer (NK) cells, and dendritic cells (DCs) can each be made from multiple progenitors under experimental circumstances. 1,2 Indeed, apparently similar DCs arise from distinct myeloid or lymphoid progenitors. 3 This new perspective raises the possibility that choices are made between multiple pathways to replenish effectors of the immune system. Thus, it is important to learn what normal and disease conditions favor particular differentiation routes.Several major categories of DCs have been found in murine bone marrow (BM). Conventional DCs (cDCs) are competent to present antigens, whereas plasmacytoid dendritic cells (pDCs) are potent producers of type I interferon. 3 The pDCs are divisible into 2 subtypes (pDC1 and pDC2) on the basis of RAG-1 expression and patterns of cytokine production. 4 Under experimental conditions, DCs are produced from stem cells, as well as lymphoid and myeloid progenitors. [3][4][5] Flk-2/flt-3 ligand and the associated Stat3 signaling pathway are important for DC differentiation; consequently, efficient progenitors bear the Flk-2/flt-3 receptor. 3 In our experience, the highest yields of pDCs are obtained from the primitive Lin Ϫ c-Kit hi Sca-1 ϩ (LSK) fraction of murine BM. 4 Two recent reports identified a Lin Ϫ Flt3 ϩ c-Kit lo -CD115 ϩ pro-DC population capable of generating pDCs and at least 2 categories of DCs. 6,7 However, greater yields of DCs were produced from more primitive progenitors, and some of those are already restricted to particular DC pathways. 7 Common lymphoid progenitors (CLPs) represent the main pathway to B lineage cells and include most progenitors dest...

CpG Promotes Cross-Presentation of Dead Cell-Associated Antigens by Pre-CD8α+ Dendritic Cells

“…Circulating hematopoietic stem cells (HSC) also contribute to the replenishment of the DC pool, and this process is favored by TLR ligands. Indeed, HSC and more differentiated progenitors are directed to differentiate into DC in vitro following LPS stimulation or in vivo following viral infection in mice as a result of TLR9 engagement (17,19). LPS also favors the retention of HSC in tissues and stimulates their local proliferation and their differentiation into DC (16).…”

“…This impairment correlates with a decrease in Ag phagocytosis (14,15). Moreover, in recent years, TLR ligands have been shown to influence hematopoiesis, favoring the retention of hematopoietic progenitors in tissues and stimulating their local proliferation and differentiation into DC (16)(17)(18)(19)(20). This could provide a boost of fresh innate immune effector cells during infections that could sustain the adaptive immune responses against the pathogens.…”

From HSC to B-Lymphoid Cells in Normal and Malignant Hematopoiesis

“…Moreover, they are capable of self/non-self discrimination through Toll-like receptors (TLR), which recognize microbial components. Mouse stem cells and early B-cell progenitors express and use TLR, a mechanism that facilitates their differentiation to the innate immune system (Nagai et al, 2006;Welner et al, 2008b;Welner et al, 2009). Recent work suggests that, as in mice, human primitive cells, including MLP, also express functional TLR (Kim et al, 2005;Sioud & Fløisand, 2007;De Luca et al, 2009;Doulatov et al, 2010).…”

CpG Inhibits Pro-B Cell Expansion through a Cathepsin B-Dependent Mechanism

“…It was recently found that hematopoietic stem cells, as well as multipotent progenitors of human and mouse origin, express TLRs and respond to their ligands by preferentially adopting a myeloid fate (10,11). B lymphocytes also express TLRs and respond to ligand binding by polyclonal activation, proliferation, and differentiation into Ab secretion.…”

“…Stimulation of common lymphoid progenitors through this receptor inhibits differentiation along the B lineage and stimulates differentiation of dendritic cells (DCs) (11). B cell progenitors express TLR9 (14), but little is known of its role in lymphopoiesis.…”