Macroautophagy in lymphatic endothelial cells inhibits T cell-mediated autoimmunity

J Exp Med. 2021 Jun 7;218(6):e20201776. doi: 10.1084/jem.20201776.


Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / immunology
  • Autoimmunity / immunology*
  • Cell Movement / immunology
  • Cells, Cultured
  • Endothelial Cells / immunology*
  • Humans
  • Immune Tolerance / immunology
  • Inflammation / immunology
  • Lymph Nodes / immunology
  • Lymphatic Vessels / immunology
  • Lysophospholipids / immunology
  • Macroautophagy / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Sphingosine / analogs & derivatives
  • Sphingosine / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology*


  • Lysophospholipids
  • sphingosine 1-phosphate
  • Sphingosine