CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment

Zicheng Hu; Yu Li; Annemarie Van Nieuwenhuijze; Hilary J Selden; Angela M Jarrett; Anna G Sorace; Thomas E Yankeelov; Adrian Liston; Lauren I R Ehrlich

doi:10.1016/j.celrep.2017.09.016

CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment

Cell Rep. 2017 Oct 3;21(1):168-180. doi: 10.1016/j.celrep.2017.09.016.

Authors

Zicheng Hu¹, Yu Li¹, Annemarie Van Nieuwenhuijze², Hilary J Selden¹, Angela M Jarrett³, Anna G Sorace⁴, Thomas E Yankeelov⁵, Adrian Liston², Lauren I R Ehrlich⁶

Affiliations

¹ Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA.
² Translational Immunology Laboratory, VIB, Leuven 3000, Belgium; Department of Microbiology and Immunology, University of Leuven, Leuven 3000, Belgium.
³ Departments of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
⁴ Departments of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Diagnostic Medicine, The University of Texas at Austin, Austin, TX 78712, USA; Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.
⁵ Departments of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Diagnostic Medicine, The University of Texas at Austin, Austin, TX 78712, USA; Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA; Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.
⁶ Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA; Livestrong Cancer Institutes, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address: lehrlich@austin.utexas.edu.

Abstract

Upon recognition of auto-antigens, thymocytes are negatively selected or diverted to a regulatory T cell (Treg) fate. CCR7 is required for negative selection of auto-reactive thymocytes in the thymic medulla. Here, we describe an unanticipated contribution of CCR7 to intrathymic Treg generation. Ccr7^-/- mice have increased Treg cellularity because of a hematopoietic but non-T cell autonomous CCR7 function. CCR7 expression by thymic dendritic cells (DCs) promotes survival of mature Sirpα^- DCs. Thus, CCR7 deficiency results in apoptosis of Sirpα^- DCs, which is counterbalanced by expansion of immature Sirpα⁺ DCs that efficiently induce Treg generation. CCR7 deficiency results in enhanced intrathymic generation of Tregs at the neonatal stage and in lymphopenic adults, when Treg differentiation is critical for establishing self-tolerance. Together, these results reveal a complex function for CCR7 in thymic tolerance induction, where CCR7 not only promotes negative selection but also governs intrathymic Treg generation via non-thymocyte intrinsic mechanisms.

Keywords: CCR7; central tolerance; chemokine receptor; dendritic cells; regulatory T cells; thymocyte development; thymus.

MeSH terms

Animals
Apoptosis / immunology
Bone Marrow Transplantation
Cell Differentiation
Cell Survival / immunology
Dendritic Cells / cytology
Dendritic Cells / immunology*
Gene Expression Regulation
Immune Tolerance*
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, CCR7 / deficiency
Receptors, CCR7 / genetics*
Receptors, CCR7 / immunology
Receptors, Immunologic / deficiency
Receptors, Immunologic / genetics
Receptors, Immunologic / immunology
Signal Transduction
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology*
Thymocytes / cytology
Thymocytes / immunology*
Thymus Gland / cytology
Thymus Gland / immunology*
Transplantation Chimera
Whole-Body Irradiation

Substances

Ccr7 protein, mouse
Ptpns1 protein, mouse
Receptors, CCR7
Receptors, Immunologic

Grants and funding

R01 AI104870/AI/NIAID NIH HHS/United States