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.

Dendritic cells (DCs) are composed of multiple subsets that play a dual role in inducing immunity and tolerance. However, it is unclear how CD205+ conventional DCs (cDCs) control immune responses in vivo. Here we generated knock-in mice with the selective conditional ablation of CD205 + cDCs. CD205 + cDCs contributed to antigenspecific priming of CD4 + T cells under steady-state conditions, whereas they were dispensable for antigen-specific CD4 + T-cell responses under inflammatory conditions. In contrast, CD205 + T cells. Although most cells use MHC I molecules to present peptides derived from endogenously synthesized proteins, DCs have the capacity to deliver exogenous antigens to the MHC I pathway, a phenomenon known as cross-presentation, that underlies the generation of cytotoxic T lymphocyte (CTL) immunity (1-3). DCs thereby play a critical role in the link between innate and adaptive immunity. Conversely, DCs are also crucial for the induction of immunological tolerance under steady-state conditions, and the mechanisms involved include recessive tolerance mediated by deletion and anergy, and dominant tolerance by maintaining the homeostasis of self-reactive CD4 + Foxp3+ naturally occurring regulatory T cells (nTregs) and de novo generation of antigen-specific CD4 + Foxp3+ inducible Tregs (iTregs) (4-7). Mouse cDCs in lymphoid organs are comprised of two major subsets, classified as CD8α + cDCs and CD8α − cDCs. CD8α + cDCs mainly reside in the T-cell zone, and CD8α − cDCs reside in the red pulp and marginal zone (2, 8). Series of in vitro and ex vivo studies reported that CD8α+ cDCs compared with CD8α− cDCs strongly generate T-helper cell type 1 (Th1) cells because of the potential high-level production of IL-12 (9). In addition, CD8α + cDCs are more efficient in the phagocytic uptake of dead cells and in the cross-presentation of cell-bound or soluble antigens on MHC I to generate CTLs than other DC subsets (9).CD205, an endocytic type I C-type lectin-like molecule that belongs to the mannose receptor family, is mainly expressed on CD8α+ cDCs and cortical thymic epithelium, as well as interdigitating DCs in cutaneous lymph nodes (LNs) derived from dermal DCs and epidermal Langerhans cells (LCs), usually at a higher level than seen on macrophages and B cells (10-13). CD205 may function as an endocytic receptor involved in the uptake of extracellular antigens. Although an endogenous ligand for CD205 has not been identified, an antigen-conjugated mAb specific for CD205 was internalized, processed in the endosomal compartment, and presented to both MHC II and MHC I for cross-presentation with high efficiency (10). Although these observations based on analyses in vitro and ex vivo provide the functions of CD205 + cDCs, their role in the immune system under physiological conditions remains unclear because of the lack of a system that selectively eliminates this cell subset in vivo.To precisely evaluate the contribution of CD205 + cDCs to the immune system, we engineered knock-in mice that express the diphtheri...

Psoriasis is a chronic inflammatory skin disease characterized mainly by epidermal hyperplasia, scaling, and erythema; T helper 17 cells have a role in its pathogenesis. Although IL-26, known as a T helper 17 cytokine, is upregulated in psoriatic skin lesions, its precise role is unclear. We investigated the role of IL-26 in the imiquimod-induced psoriasis-like murine model using human IL-26 transgenic mice. Erythema symptoms induced by daily applications of imiquimod increased dramatically in human IL-26 transgenic mice compared with controls. Vascularization and immune cell infiltration were prominent in skin lesions of human IL-26 transgenic mice. Levels of fibroblast growth factor (FGF) 1, FGF2, and FGF7 were significantly upregulated in the skin lesions of imiquimod-treated human IL-26 transgenic mice and psoriasis patients. In vitro analysis demonstrated that FGF1, FGF2, and FGF7 levels were elevated in human keratinocytes and vascular endothelial cells following IL-26 stimulation. Furthermore, IL-26 acted directly on vascular endothelial cells, promoting proliferation and tube formation, possibly through protein kinase B, extracellular signaleregulated kinase, and NF-kB pathways. Moreover, similar effects of IL-26 were observed in the murine contact hypersensitivity model, indicating that these effects are not restricted to psoriasis. Altogether, our data indicate that IL-26 may be a promising therapeutic target in T cellemediated skin inflammation, including psoriasis.

Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγnull mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.

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