Ly49Q ligand expressed by activated B cells induces plasmacytoid DC maturation

Abstract

Ly49Q, a type II C-type lectin expressed on mouse plasmacytoid DC (pDC), contains a single carbohydrate recognition domain in its extracellular region and an ITIM in its cytoplasmic domain. We have identified the MHC class I molecule H-2K b as a Ly49Q ligand, confirming prior reports. Although H-2K b is expressed on essentially all hematopoietic cells, we found that only CpG-stimulated B cells were able to activate Ly49Q. This discovery correlated with our finding that although H-2K b forms clusters on CpG-activated B cells, it is diffusely expressed on resting B cells. Furthermore, CpG-stimulated, but not resting, B cells up-regulated co-stimulatory molecules on pDC. This finding was confirmed by the fact that binding by anti-Ly49Q mAb to Ly49Q led to pDC maturation in vitro. Our results suggest that clustered H-2K b on activated B cells act as ligands for Ly49Q and induce pDC maturation in vitro.Key words: B cell . IFN . Ly49Q . MHC class I . plasmacytoid DC Supporting Information available online IntroductionPlasmacytoid DC (pDC) are a specialized subset of DC responsible for initiating immune responses to viruses [1,2]. They develop in the bone marrow and circulate in the blood before migrating into lymphoid and non-lymphoid organs [1,2], and they exhibit increased recruitment into sites of inflammation [3,4]. pDC detect viruses through TLR7 and TLR9 [5]. In response, they produce large amounts of type I IFN and pro-inflammatory chemokines to direct the innate and adaptive immune responses and to promote cytotoxicity in NK cells and CD8 1 T cells [6]. pDC have also been implicated in promoting monocyte-derived DC maturation, presenting antigen to T cells, inducing Th1 polarization [1,2], and promoting B-cell differentiation into 1344Ab-producing plasma cells [7,8]. However, there is very little information about how other cells affect pDC function.Ly49Q is a member of the Ly49 family of mouse NK receptors that is expressed on pDC but not on NK cells or NKT cells [9][10][11]. This receptor family belongs to a group of type II integral membrane proteins that contain external domains homologous to the super-family of Ca-dependent lectins [12]. The Ly49 family comprises two subclasses, one of which harbors an ITIM in the cytoplasmic domain, which recruits the intracellular tyrosine phosphatases SHP-1 or SHP-2 [13][14][15]. Members of the other subclass lack an ITIM, have a charged residue in the transmembrane domain, and deliver activating signals via the adapter protein DAP12 [16]. Inhibitory Ly49 molecules primarily bind MHC class I ligands [17,18], whereas the ligands for activating Ly49 molecules also include MHC class I-like molecules expressed by viruses. For example, Ly49H binds the m157 gene product of mouse cytomegalovirus [19,20]. A fine balance between inhibitory and activating signals regulates the cytokine production and cytolytic activity of NK cells [21][22][23].The presence of an ITIM in the cytoplasmic domain of Ly49Q suggests that it -like the Ly49 family members expressed on NK cells -might f...

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“…On pDCs, Ly49Q was shown to bind H-2K b , a classical MHC class I molecule (Tai et al, 2007), which enhances pDC function (Tai et al, 2008). Ly49Q also binds the Ly49Q ligand that stimulates maturation of pDCs (Toma-Hirano et al, 2009). Lack of Ly49Q expression defines two subsets of pDCs (Ly49Q + and Ly49Q − DCs) (Kamogawa-Schifter et al, 2005).…”

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“…Two of the 11 known genes were expressed on cells other than NK cells, notably Ly49Q which is found on myeloid cells and plasmacytoid dendritic cell (pDCs) subsets (Kamogawa-Schifter et al, 2005), and plays a role in maturation of these pDCs (Toma-Hirano et al, 2009) and activation of osteoclasts (Hayashi et al, 2010). Ly49B also is found on CD11b+ myeloid cells including macrophages, granulocytes, and mast cells, and there has been one report of Ly49B on activated NK and an iNK T cell line.…”

Inhibitory C-type lectin receptors in myeloid cells

“…H-2K b has been identified as a high affinity class I MHC cis -ligand of Ly49Q [76]. Clusters of this ligand on activated B lymphocytes were able to up-regulate the expression of co-stimulatory molecules on pDCs and induce their maturation [77]. Counter-intuitively, Ly49q-H2K b interactions positively regulated TLR signals and subsequent cytokine production in pDCs.…”