Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

J Autoimmun. 2016 Dec;75:141-149. doi: 10.1016/j.jaut.2016.08.002. Epub 2016 Aug 16.

Abstract

In the thymus, antigen presenting cells (APCs) namely, medullary thymic epithelial cells (mTECs) and thymic dendritic cells (tDCs) regulate T cell tolerance through elimination of autoreactive T cells and production of thymic T regulatory (tTreg) cells. How the different APCs in the thymus share the burden of tolerazing the emerging T cell repertoire remains unclear. For example, while mutations that inhibit mTEC development or function associate with peripheral autoimmunity, the role of tDCs in organ-specific autoimmunity and tTreg cell production remains controversial. In this report we used mice depleted of mTECs and/or CD8α+ DCs, to examine the contributions of these cell populations in thymic tolerance. We found that while mice depleted of CD8α+ DCs or mTECs were normal or developed liver inflammation respectively, combined depletion of mTECs and CD8α+ DCs resulted in overt peripheral autoimmunity. The autoimmune manifestations in mice depleted of both mTECs and CD8α+ cDCs associated with increased percentages of CD4+ and CD8+ T cells in the thymus. In contrast, while mTEC depletion resulted in reduced percentages of tTreg cells, no additional effect was observed when CD8α+ DCs were also depleted. These results reveal that: 1) mTECs and CD8α+ DCs cooperatively safeguard against peripheral autoimmunity through thymic T cell deletion; 2) CD8α+ DCs are dispensable for tTreg cell production, whereas mTECs play a non-redundant role in this process; 3) mTECs and CD8α+ DCs make unique contributions to tolerance induction that cannot be compensated for by other thymic APCs such as migratory SIRPα+ or plasmacytoid DCs.

Keywords: Autoimmunity; Dendritic cells; Medullary thymic epithelial cells; Regulatory T cells.

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Autoimmunity / immunology
  • CD8 Antigens / immunology*
  • CD8 Antigens / metabolism
  • Central Tolerance / immunology*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Epithelial Cells / immunology*
  • Epithelial Cells / metabolism
  • Flow Cytometry
  • Immune Tolerance / immunology
  • Lymphocyte Depletion
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Immunological
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Thymus Gland / metabolism

Substances

  • CD8 Antigens
  • CD8 antigen, alpha chain
  • Ptpns1 protein, mouse
  • Receptors, Immunologic