DC Function CD137 Expression and Signaling

Dendritic cells acquire, internalize, process, and present antigens in the form of protease cleaved peptides derived from extracellular or intracellular antigens (Steinman, 1991). Processed peptides are then displayed in the context of MHC molecules on the cell surface and prime T cells bearing the appropriate peptide-specific TCR. The acquisition and presentation of antigens by dendritic cells is restricted to different stages of their development, the former function being carried out by immature dendritic cells, while the latter is thought to be carried out by mature dendritic cells (Steinman et al., 1999). During maturation, DC increase their expression of MHC class II molecules as well as several lig-ands (CD40, CD80, and CD86) for costimulatory receptors expressed on T cells (Steinman et al., 1999). By doing so, DC acquire the ability to antigen prime and activate T cells. A key component in the establishment of immunity to pathogens is the ability of dendritic cells to recognize pathogenic microorganisms through a conserved family of Toll-like Receptors (TLR). TLR recognize specific ligands produced by bacteria such as lipopolysaccharides, flagellin, and CpG nucleotides (Medzhitov and Janeway, 1999); the triggering of these receptors represents a major physiological mechanism through which dendritic cells undergo maturation (Medzhitov and Janeway, 2000). It has been suggested that prior to infection or inflammation immature dendritic cells remain in a "steady state" and maintain peripheral tolerance self antigens and environmental proteins (Steinman and Nussenzweig, 2002). Support for this point of view stems from two quarters. Peripheral tolerance can be initiated following deletion of autoreactive T cells via a process that is akin to the establishment of central tolerance in the thymus. Many dendritic cells, particularly those in the T cell areas, express an adsorptive endocy-tosis receptor termed DEC-205 on their surface, the natural ligand for which is not known (Inaba et al., 1995). Hawiger and colleagues used an antigen (HEL) to target DC in the form of an HEL-DEC-205 fusion protein. The cytoplasmic domain of DEC-205 contains an EDE tri-acidic amino acid targeting sequence, thus allowing targeting of the receptor-HEL fusion protein to MHC class Il-containing compartments. Compared with normal HEL uptake and antigen processing, fusion protein targeting of HEL was found to be 30-100 fold more efficient (Hawiger et al.,

2001). When HEL specific TCR transgenic T cells were exposed to these immature dendritic cells the T cells proliferated during the first week post-stimulation. However, the majority of proliferating T cells were deleted, thus inducing a state of tolerance to HEL in the remaining antigen specific T cells even following vaccination with complete Freund's adjuvant containing HEL peptides. However, tolerance could be overcome if, at the time of exposure of dendritic cells to antigen, the DC received a maturation signal (Hawiger et al., 2001). In agreement with these studies are several reports demonstrating that bone marrow dendritic cells can mediate peripheral deletion or anergy in situ (Steinman and Nussenzweig,

Mouse spleen and bone marrow derived DC can express CD137 receptors on their surface (Futagawa et al., 2002; Wilcox et al., 2002). It has also been shown that human tonsil follicular DC express high levels of CD137 on their surface (Lindstedt et al., 2003). We find that all phenotypic subsets of mouse splenic DC have the capacity to express CD137 following viral infection, but that DC expressing the highest level of CD137+ bear the phenotype of a myeloid-derived, immature dendritic cell (Maris et al., submitted). Following CD137 receptor crosslinking, either by 4-1BB ligand expressing tumor cells or an anti-mouse CD137 mAb, splenic dendritic cells produce and secrete IL-6 and IL-12 (Futagawa

Figure 5.11. Adoptive transfer of DC reverses anti-CD137-induced suppression. One million bone marrow-derived DC were injected I.V into a group of 26 week-old NZB/W F1 mice injected with anti-CD137 mAbs 4 weeks earlier (filled squares). A second group of anti-CD137 mAbs did not receive DC (filled triangles). The mice were bled weekly and serum anti-dsDNA antibody titers were determined by ELISA.

Anti-CD137 T Weeks

Figure 5.11. Adoptive transfer of DC reverses anti-CD137-induced suppression. One million bone marrow-derived DC were injected I.V into a group of 26 week-old NZB/W F1 mice injected with anti-CD137 mAbs 4 weeks earlier (filled squares). A second group of anti-CD137 mAbs did not receive DC (filled triangles). The mice were bled weekly and serum anti-dsDNA antibody titers were determined by ELISA.

et al., 2002; Wilcox et al., 2002). IL-6 is an anti-inflammatory Th2 cytokine whose expression and function is prominent in myeloid cell development, humoral immune responses, and in certain autoimmune diseases. These include EAE (Ishihara and Hirano, 2002; Samoilova et al., 1998), RA (Hata et al., 2004; Hwang et al., 2004; Nishimoto and Kishimoto, 2004), juvenile diabetes (Scholin et al., 2004; Vozarova et al., 2001), and SLE (Ohteki et al, 1993; Suzuki et al, 1993; Tang etal., 1991). IL-12 is a pro-inflammatory cytokine that promotes the development of Th1 mediated immune responses, it induces T cells to produce IFN-y and drives both innate and adaptive anti-tumor immune responses (Gao etal., 2003; Kodama et al., 1999; Martinet et al., 2002; Parihar et al., 2002; Smyth et al., 2000; Uekusa et al., 2002). How these two opposing cytokines are coordinately regulated following CD137 signaling, and what their physiological roles are in dendritic cell biology and T cell immunity remains to be determined.

Anti-CD137 induced suppression of SLE can be reversed by adoptively transferring dendritic cells from untreated NZB/W F1 mice into anti-CD137 treated autoimmune mice (Foell et al., 2003; Figure 5.11). This observation supports the notion that CD4 helper T cells are not deleted or permanently impaired, but that they may have failed to receive the required sequence of signals from dendritic cells during antigen priming. If true, then dendritic cells rather than T cells are the primary targets of anti-CD137 mAbs, and signals delivered to the dendritic cell through CD137 block its ability to antigen prime CD4 T cells.

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