Search
Close
Search
Advanced Search
Search Menu
AI Discovery Assistant

Abstract

Clonal deletion of auto-reactive thymocytes is crucial for establishing central tolerance. To mediate negative selection, thymic epithelial cells and dendritic cells (DCs) present self-antigens to thymocytes. Thymocytes that undergo high avidity TCR-mediated interactions with self-peptide:MHC complexes undergo apoptosis to prevent autoimmunity. DCs have been shown to be essential for negative selection. However, the molecular mechanisms governing interactions between thymocytes and DCs are not well characterized. In this study, we find that a chemokine receptor, CCR4, is required for efficient clonal deletion. CCR4 is expressed by post-positive selection thymocytes; CCR4 ligands are expressed by thymic DCs, suggesting CCR4 signaling could mediate interactions between these cell types. Using bone marrow chimeras, we find that CCR4 deficient polyclonal thymocytes fail to undergo efficient clonal deletion, but increase the differentiation to Tregs. While CCR4 deficient OTII TCR transgenic thymocytes also display defects in clonal deletion to endogenous antigens, they undergo efficient deletion to their high affinity ovalbumin antigen. This suggests that CCR4 is not required for TCR-signaling mediating apoptosis, but is required for efficient interactions with thymic DCs that present rare or low affinity antigens. Consistent with defects in clonal deletion, CCR4 deficient mice are prone to autoimmunity, demonstrating that CCR4 is essential for central tolerance.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://dbpia.nl.go.kr/pages/standard-publication-reuse-rights)
Issue Section:
Immune Regulation by Cytokines and Chemokines Session
You do not currently have access to this article.
Download all slides