Differentiation, Maturation, and Survival of Dendritic Cells by Osteopontin Regulation

Abstract

Dendritic cells (DCs) play critical roles in innate immunity and adaptive immunity (4). Immature DCs reside in peripheral tissues, where they serve as sentinels for foreign antigens and microbial pathogens. Upon activation, immature DCs undergo maturation and migrate to the lymph nodes. During maturation, DCs acquire an enhanced capacity to form and accumulate peptides, major histocompatibility complex (MHC) class II molecules, costimulatory molecules (such as CD40, CD80, and CD86), and antigens of unknown functions (such as CD83 and DC-LAMP) (10). Mature DCs can prime naïve T cells and initiate primary T-cell-mediated immune responses (4). In addition, there is increasing evidence that DCs in situ induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in peripheral tissues (4, 31). Thus, DCs play a crucial role during the initiation and regulation of immune responses. Recently, we and others reported that DCs are essential for granuloma formation against bacterial antigens in animal models (12,33,36).Osteopontin (OPN), also known as early T-lymphocyte activation-1 (Eta-1), is a phosphoprotein that contains arginineglycine-aspartate (RGD). Although OPN is classified as an extracellular matrix (ECM) protein, OPN has only recently been shown to be an important component of early cellular immune responses (18). OPN has various functions in chemotaxis for immune cells, tumor metastasis, neovascularization, and host defense, including control of nitric oxide production, control of infection, and control of cell adhesion (3,5,9,21,25). These mechanisms are regulated by posttranslational modifications, such as cleavage by thrombin, addition of a glucose chain, and phosphorylation. Various immunological disorders are associated with high levels of OPN expression (8,15). Analyses of OPN-deficient mice revealed that OPN plays an important immunological role in granuloma formation (23), acid-fast bacillus disease (21), and carcinoma metastasis (5). The role of OPN in inflammation suggests that ECM-related proteins may function as pleiotropic cytokines to regulate immune responses. Activated macrophages, lymphocytes, and natural killer (NK) cells produce OPN in response to various stimuli (23). However, there are no reports of the effects of OPN on DCs, with the exception of a single report of the migratory effect of OPN on cutaneous Langerhans cells and DCs in a mouse allergic cutaneous hypersensitivity model (34). The direct effect of OPN on the development and activation of DCs has not been clarified. Thus, we sought to characterize the functional interaction between OPN and DCs by examining the effects of OPN on differentiation, maturation, and function of human monocyte-derived immature and mature DCs. We report here that human monocyte-derived dendritic cell (Mo-DC) can produce OPN that enhances differentiation, maturation, and survival of DCs by autocrine and/or paracrine pathways. MATERIALS AND METHODSReagents. Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) ...

Osteopontin: Role in immune regulation and stress responses

“…OPN is highly expressed in immature DCs but production decreases during maturation (Kawamura et al, 2005). This research demonstrated that OPN acts in an autocrine and/or paracrine manner to induce DC maturation because treatment with an anti-OPN antibody blocked LPS-induced human DC maturation.…”

“…As it is for other inflammatory cells, OPN is a survival factor for dendritic cells. Blockade of OPN with anti-OPN antibody reduces co-stimulatory molecule and class II molecule expression on human monocyte-derived DCs and promotes apoptosis of mature DCs (Kawamura et al, 2005). OPN was implicated in DC migration in research demonstrating that OPN initiates Langerhans cells/dendritic cell emigration from the epidermis and attracts them to draining lymph nodes by interacting with CD44 and α v integrin (Weiss et al, 2001).…”

Osteopontin regulates development and function of invariant natural killer T cells

“…1A). OPN is involved in the survival of cells (16) and differentiation and development of dendritic cells (DCs) (19). Thus, we examined whether OPN deficiency impacted the development of iNKT cells.…”

Osteopontin attenuation of dextran sulfate sodium-induced colitis in mice

“…12 OPN is secreted by dendritic cells, activated macrophages, T lymphocytes, and subsequently by proliferating fibroblasts during reparative matrix formation. [13][14][15] We have shown that OPN is upregulated in epithelial cells of the intestinal mucosa during experimental colitis. 16 We have also shown that OPN is chemoattractive for neutrophils but not involved in phagocytosis or generation of reactive oxygen species.…”