Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells

Nat Commun. 2018 Mar 28;9(1):1262. doi: 10.1038/s41467-018-03619-9.

Abstract

Medullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4+ thymocyte crosstalk regulates the thymus homing of SHPS-1+ conventional DCs (cDC), plasmacytoid DCs (pDC) and macrophages. This homing process is controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently, Ltα-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-κB subunits and increased thymic recruitment of cDCs, pDCs and macrophages. This enhanced migration depends mainly on the chemokine receptor CCR2, and increases thymic clonal deletion. Altogether, this study identifies a fine-tuning mechanism of T cell repertoire selection and paves the way for therapeutic interventions to treat autoimmune disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology*
  • Antigens / immunology
  • Bone Marrow Cells / immunology
  • Chemokines / immunology
  • Clonal Deletion*
  • Coculture Techniques
  • Dendritic Cells / immunology
  • Female
  • Gene Deletion
  • Immune Tolerance
  • Ligands
  • Lymphotoxin-alpha / metabolism*
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Confocal
  • NF-kappa B / metabolism
  • Receptors, CCR2 / metabolism
  • T-Lymphocytes / immunology
  • Thymocytes / immunology
  • Thymus Gland / immunology*

Substances

  • Antigens
  • Ccr2 protein, mouse
  • Chemokines
  • Ligands
  • Lymphotoxin-alpha
  • NF-kappa B
  • Receptors, CCR2