DEC-205 is an endocytic receptor expressed by a distinct CD8 alpha+ dendritic cell subpopulation. Targeting of proteins to DEC-205 through chimeric antibody constructs causes clonal deletion or anergy of antigen-specific CD4+ and CD8+ T cells in immunologically normal mice. In NOD mice, a mouse model for autoimmune diabetes, beta cell-specific CD8+ T cells can be depleted by anti-DEC antigen treatment (Mukhopadhaya A, et al. PNAS 2008). Using DEC-205 targeting, we have now determined that in autoimmune NOD mice, CD8 DCs are not able to induce CD4+ T cell tolerance. Antigen targeted to NOD CD8 DCs does not induce deletion, anergy or regulatory T cells (the 3 main mechanisms of peripheral T cell tolerance), but instead induces expansion and IFN gamma production in the T cells. We are interested in what immune pathways may be important for restoring tolerance in this setting. CD40/CD40L interactions are one pathway that may be important: when a blocking antibody specific for anti-CD40L was given with anti-DEC-205 antigen, T cell responses were more tolerogenic (less expansion and IFN gamma production). This work is now under review. CD11b+ dendritic cells express DCIR2 on their surface, and antibodies specific for DCIR2 can be used to target antigens to this DC subset. We are now measuring BDC2.5 TCR transgenic T cell responses after stimulation in vivo with anti-DCIR2-targeted BDC peptide in NOD mice. We are also testing whether this antibody-antigen combination can alter diabetes development. In addition, we have compared gene expression in beta cell-specific T cells after in vivo stimulation with either DEC205+ or DCIR2+ DCs.
|Hotta-Iwamura, Chie; Tarbell, Kristin V (2016) Type 1 diabetes genetic susceptibility and dendritic cell function: potential targets for treatment. J Leukoc Biol 100:65-80|
|Price, Jeffrey D; Tarbell, Kristin V (2015) The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases. Front Immunol 6:288|
|Price, Jeffrey D; Hotta-Iwamura, Chie; Zhao, Yongge et al. (2015) DCIR2+ cDC2 DCs and Zbtb32 restore CD4+ T cell tolerance and inhibit diabetes. Diabetes :|
|Price, Jeffrey D; Beauchamp, Nicole M; Rahir, Gwendoline et al. (2014) CD8+ dendritic cell-mediated tolerance of autoreactive CD4+ T cells is deficient in NOD mice and can be corrected by blocking CD40L. J Leukoc Biol 95:325-36|
|Mukherjee, Gayatri; Geliebter, Ari; Babad, Jeffrey et al. (2013) DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of diabetogenic CD8âº T cells independently of PD-1 and PD-L1. Int Immunol 25:651-60|
|Gardner, James M; Metzger, Todd C; McMahon, Eileen J et al. (2013) Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4âº T cells. Immunity 39:560-72|