The CD8α+ Dendritic Cell Is Responsible for Inducing Peripheral Self-Tolerance to Tissue-associated Antigens

TLDR

Peripheral self‑tolerance is maintained by cross‑presentation of tissue‑associated antigens by bone‑marrow derived cells that stimulate proliferation and deletion of self‑reactive CD8 T cells, a process termed cross‑tolerance. The study aims to identify the cell type that induces cross‑tolerance, hypothesizing it to be a CD8α+ dendritic cell. Transgenic mice expressing YFP‑linked CTL epitopes under the rat insulin promoter were generated, and a gB‑specific hybridoma was used to detect antigen presentation by pancreatic lymph node cells. A CD11c+CD8α+ dendritic cell was shown to mediate cross‑tolerance, indicating that CD8α+ DCs are crucial for both tolerance and immunity to cell‑associated antigens.

Abstract

We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow–derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8α+ dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced β-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c+CD8α+ cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8α+ DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self.