CCR4 promotes medullary entry and thymocyte-Dendritic cell interactions required for central tolerance

Zicheng Hu, Jessica N. Lancaster, Chayanit Sasiponganan, Lauren I.R. Ehrlich

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigenpresenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use twophoton time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance.

Original languageEnglish (US)
Pages (from-to)1947-1965
Number of pages19
JournalJournal of Experimental Medicine
Volume212
Issue number11
DOIs
StatePublished - Oct 19 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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