CCR4 and CCR7 differentially regulate thymocyte localization with distinct outcomes for central tolerance

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Abstract

Central tolerance ensures autoreactive T cells are eliminated or diverted to the regulatory T cell lineage, thus preventing autoimmunity. To undergo central tolerance, thymocytes must enter the medulla to test their TCRs for autoreactivity against the diverse self-antigens displayed by antigen presenting cells (APCs). While CCR7 is known to promote thymocyte medullary entry and negative selection, our previous studies implicate CCR4 in these processes, raising the question of whether CCR4 and CCR7 play distinct or redundant roles in central tolerance. Here, synchronized positive selection assays, 2-photon timelapse microscopy, and quantification of TCR-signaled apoptotic thymocytes, demonstrate that CCR4 and CCR7 promote medullary accumulation and central tolerance of distinct post-positive selection thymocyte subsets in mice. CCR4 is upregulated within hours of positive selection signaling and promotes medullary entry and clonal deletion of immature post-positive selection thymocytes. In contrast, CCR7 is expressed several days later and is required for medullary localization and negative selection of mature thymocytes. In addition, CCR4 and CCR7 differentially enforce self-tolerance, with CCR4 enforcing tolerance to self-antigens presented by activated APCs, which express CCR4 ligands. Our findings show that CCR7 expression is not synonymous with medullary localization and support a revised model of central tolerance in which CCR4 and CCR7 promote early and late stages of negative selection, respectively, via interactions with distinct APC subsets.

Data availability

All data in this study are included in the source data excel file 'Source data_revised'. Data for individual components of figures are found on the corresponding tabs in the spreadsheet.

Article and author information

Author details

Yu Li

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
Pablo Guaman Tipan

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
Hilary J Selden

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
Jayashree Srinivasan

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9478-7518
Laura P Hale

Department of Pathology, Duke University, Durham, United States

Competing interests
The authors declare that no competing interests exist.
Lauren IR Ehrlich

Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States

For correspondence
lehrlich@austin.utexas.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1697-1755

Funding

National Institutes of Health (R01AI104870)

Lauren IR Ehrlich

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (# AUP-2019-00034) at the University of Texas at Austin.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.