Live-cell imaging reveals the relative contributions of antigen-presenting cell subsets to thymic central tolerance

Nat Commun. 2019 May 17;10(1):2220. doi: 10.1038/s41467-019-09727-4.

Abstract

Both medullary thymic epithelial cells (mTEC) and dendritic cells (DC) present tissue-restricted antigens (TRA) to thymocytes to induce central tolerance, but the relative contributions of these antigen-presenting cell (APC) subsets remain unresolved. Here we developed a two-photon microscopy approach to observe thymocytes interacting with intact APCs presenting TRAs. We find that mTECs and DCs cooperate extensively to induce tolerance, with their relative contributions regulated by the cellular form of the TRA and the class of major histocompatibility complex (MHC) on which antigen is presented. Even when TRA expression is restricted to mTECs, DCs still present self-antigens at least as frequently as mTECs. Notably, the DC subset cDC2 efficiently acquires secreted mTEC-derived TRAs for cross-presentation on MHC-I. By directly imaging interactions between thymocytes and APCs, while monitoring intracellular signaling, this study reveals that distinct DC subsets and AIRE+ mTECs contribute substantially to presentation of diverse self-antigens for establishing central tolerance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen Presentation / immunology
  • Autoantigens / immunology
  • Autoantigens / metabolism
  • Bone Marrow Transplantation
  • Cell Separation / methods
  • Central Tolerance / immunology*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Epithelial Cells / immunology
  • Female
  • Flow Cytometry / methods
  • Intravital Microscopy / methods
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence, Multiphoton / methods
  • T-Lymphocytes, Regulatory / immunology
  • Thymocytes / immunology*
  • Thymocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Transcription Factors / immunology
  • Transcription Factors / metabolism
  • Transplantation Chimera / immunology

Substances

  • APECED protein
  • Autoantigens
  • Transcription Factors