Plasmacytoid Dendritic Cells Are Crucial for the Initiation of Inflammation and T Cell Immunity In Vivo

Abstract

Plasmacytoid dendritic cells (pDCs) are characterized as type I interferon-producing cells that engage endosomal toll-like receptors (TLRs) and exclusively express sialic acid binding Ig-like lectin (Siglec)-H. However, their role in vivo remains unclear. Here we report a critical role for pDCs in the regulation of inflammation and T cell immunity in vivo by using gene-targeted mice with a deficiency of Siglec-H and conditional ablation of pDCs. pDCs were required for inflammation triggered by a TLR ligand as well as by bacterial and viral infections. pDCs controlled homeostasis of effector and regulatory CD4(+) T cells. Upon antigenic stimulation and microbial infection, pDCs suppressed the induction of CD4(+) T cell responses and participated in the initiation of CD8(+) T cell responses. Furthermore, Siglec-H appeared to modulate the function of pDCs in vivo. Thus, our findings highlight previously unidentified roles of pDCs and the regulation of their function for the control of innate and adaptive immunity.

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

“…In line with our previous reports, 31,32 pDC-ablated mice that express DTR under the control of the Siglech gene showed almost complete and specific elimination of CD11c int BST2 þ pDCs, which expressed B220 but not CD11b, among CD45.2 þ CD64 À leukocytes in the spleen (Spl) and MLN as well as colonic LP after single DT injection ( Figure 1; data not shown). On the other hand, pDC-ablated mice had normal frequency of CD11c high BST2 À cDCs in these tissues compared with wildtype (WT) mice (Figure 1).…”

“…We have previously shown that pDCs could be the primary inflammatory cells to produce cytokines upon recognition of appropriate endosomal TLR ligands and viral components for the induction of systemic inflammation. 31,32 Collectively, these findings suggest that pDCs are required for initiation of DSS-induced colonic inflammation and tissue damage possibly mediated through the control of mucosal production of proinflammatory cytokines. On the other hand, Mizuno et al 39 have recently suggested that CCR9 þ pDCs in the small intestine (SI) suppress the development of murine spontaneous intestinal inflammation as CCR9 þ pDCs preferentially resided in the SI in the steady state, and Ccr9 À / À Rag-2 À / À mice developed more severe ileitis compared with Rag-2 À / À mice when these mice were adoptively transferred with CD4 þ CD45RB high T cells, although they did not assess the direct contribution …”

“…31,32 In this study, we report that pDCs are requisite for the development of DSS-induced colitis using pDC-ablated mice. We further demonstrate that the accumulation of pDCs into LP has a crucial role in the recruitment of inflammatory monocytes/macrophage and cDCs into the inflamed colon, and that amplify the 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. Although we would not absolutely rule out the possibility that some minor unidentified populations of Siglec-H þ hematopoietic cells affecting extent and severity of acute colitis might be ablated in pDC-ablated mice, the amelioration of clinical symptom of acute colitis in pDCablated mice was overcome by reconstitution with pDCs.…”

“…The following 8-12-week-old female mice were used in this study: C57BL/6 (Clea Japan, Tokyo, Japan), B6.CD45.1 (Charles River Laboratories, Portage, MI), B6.FVB-Tg Itgax À DTR/EGFP Lan/J (CD11c-DTR/EGFP) 33 (referred to as cDC-ablated mice), and B6.Ifnar1 À / À mice. 34 B6.Cg-Siglech otm1.1Ksat4 mice (B6.Siglec-H-DTR mice) generated as described previously 31 were deposited in RIKEN BioResource Center (accession number; RBRC05658), and their littermates were used as WT mice. For the systemic ablation of cDCs or pDCs, B6.CD11c-DTR/EGFP mice or B6.Siglec-H-DTR mice were intraperitoneally (i.p.)…”