DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of cognate CD8+ T cells independently of the PD-1 pathway (123.19)

Abstract

Abstract Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Cytotoxic CD8+ T cells specific for beta cell antigens are a main contributor to T1D development. CD8+ T cells specific for insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) epitopes have been implicated in T1D development in both patients and NOD mice. Targeted delivery to steady-state dendritic cells (DCs) of a beta cell peptide mimotope linked to anti-DEC-205 leads to deletional tolerance of transferred cognate CD8+ T cells in NOD mice. Treatment with anti-DEC-205 linked to NRP-V7, a superagonist mimotope of IGRP206-214, selectively deleted endogenous IGRP206-214-specific T cells, a highly prevalent specificity in NOD mice, and showed promise in T1D prevention. Simultaneous treatments with anti-DEC-205/InsI9, a mimotope peptide of the CD8+ T cell insulin epitope InsB15-23, and anti DEC-205/NRP-V7 are being held to study the effect of targeting multiple CD8+ T cell specificities on T1D prevention. Investigation of the operative tolerance mechanisms revealed that antibody blockade of the PD-1 pathway, often implicated in DC- mediated induction of peripheral tolerance, could not inhibit the deletion of transferred T cells by DEC-205-mediated targeting of their antigen to steady- state DC. Involvement of the CTLA-4 or Fas pathways will be probed to further study the molecular mechanism of tolerance induction. .