DEC-205-mediated antigen targeting to steady-state dendritic cells induces deletion of diabetogenic CD8⁺ T cells independently of PD-1 and PD-L1.

Abstract

CD8⁺ T cells specific for islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) have been implicated in type 1 diabetes in both humans and non-obese diabetic (NOD) mice, in which T cells specific for IGRP₂₀₆₋₂₁₄ are highly prevalent. We sought to manipulate these pathogenic T cells by exploiting the ability of steady-state dendritic cells (DCs) to present antigens in a tolerogenic manner. The endocytic receptor DEC-205 was utilized to deliver an IGRP₂₀₆₋₂₁₄ mimotope to DCs in NOD mice, and the impact of this delivery on a polyclonal population of endogenous islet-reactive cognate T cells was determined. Assessment of islet-infiltrating CD8⁺ T cells showed a decrease in the percentage, and the absolute number, of endogenous IGRP₂₀₆₋₂₁₄-specific T cells when the mimotope was delivered to DCs, compared with delivery of a specificity control. Employing an adoptive transfer system, deletion of CD8⁺ T cells as a result of DEC-205-mediated antigen targeting was found to occur independently of programmed death-1 (PD-1) and its ligand (PD-L1), both often implicated in the regulation of peripheral T-cell tolerance. Given its promise for the manipulation of self-reactive polyclonal T cells demonstrated here, the distinctive characteristics of this antigen delivery system will be important to appreciate as its potential as an intervention for autoimmune diseases continues to be investigated.

• Authors: Gayatri Mukherjee, Ari Geliebter, Jeffrey Babad, Pere Santamaria, David V Serreze, Gordon J Freeman, Kristin V Tarbell, Arlene Sharpe, Teresa P DiLorenzo
• Journal: International immunology (Int Immunol) Vol. 25 Issue 11 Pg. 651-60 (Nov 2013) ISSN: 1460-2377 [Electronic] England
• PMID: 24021877 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Antigens
• Antigens, CD
• B7-H1 Antigen
• Cd274 protein, mouse
• DEC-205 receptor
• Lectins, C-Type
• Minor Histocompatibility Antigens
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Receptors, Cell Surface

Topics

• Animals
• Antibodies (immunology)
• Antigen-Antibody Reactions
• Antigens (immunology)
• Antigens, CD (immunology)
• B7-H1 Antigen (metabolism)
• CD8-Positive T-Lymphocytes (cytology, immunology)
• Dendritic Cells (cytology, immunology)
• Lectins, C-Type (immunology)
• Lymphocyte Count
• Mice
• Mice, Inbred NOD
• Mice, Transgenic
• Minor Histocompatibility Antigens
• Programmed Cell Death 1 Receptor (metabolism)
• Receptors, Cell Surface (immunology)