We use chimeric antibodies to deliver antigens to specific DC subsets in vivo. Compared to responses elicited by DEC205+ DCs, DCIR2+ DCs are able to induce a more tolerogenic response in self-specific T cells, characterized by less expansion, increased apoptosis and less IFN-gamma even in this chronic autoimmune context. In addition, anti-DCIR2-targeted islet antigen inhibits diabetes development. By comparing gene expression in beta cell-specific T cells early after in vivo stimulation with either DEC205+ or DCIR2+ DCs, we have identified genes that are expressed at higher levels in T cells stimulated with the more tolerogenic DCIR2+ DCs including the transcriptional regulator zbtb32. Overexpression of zbtb32 in T cells elicits a response similar to DCIR2 DC stimulation, with decreased expansion, IFN gamma production and inhibition of diabetes development. We are now characterizing NOD zbtb32 knockout mice we produced with CRISPR directly into the NOD background to determine what effect loss of this regulator has on T cell responses and diabetes.

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6
Fiscal Year
2017
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Name
U.S. National Inst Diabetes/Digst/Kidney
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Hotta-Iwamura, Chie; Benck, Charles; Coley, William D et al. (2018) Low CD25 on autoreactive Tregs impairs tolerance via low dose IL-2 and antigen delivery. J Autoimmun 90:39-48
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 CD8? 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 CD4? T cells. Immunity 39:560-72