Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells

Eric F. Tewalt, Jarish N. Cohen, Sherin J. Rouhani, Cynthia J. Guidi, Hui Qiao, Shawn P. Fahl, Mark R. Conaway, Timothy P. Bender, Kenneth S. Tung, Anthony T. Vella, Adam J. Adler, Lieping Chen, Victor H. Engelhard

Research output: Contribution to journalArticlepeer-review

Abstract

Lymphatic endothelial cells (LECs) induce peripheral tolerance by direct presentation to CD8 T cells (TCD8).We demonstrate that LECs mediate deletion only via programmed cell death-1 (PD-1) ligand 1, despite expressing ligands for the CD160, B- and T-lymphocyte attenuator, and lymphocyte activation gene-3 inhibitory pathways. LECs induce activation and proliferation of T CD8, but lack of costimulation through 4-1BB leads to rapid high-level expression of PD-1, which in turn inhibits up-regulation of the high-affinity IL-2 receptor that is necessary for TCD8 survival. Rescue of tyrosinase-specific TCD8 by interference with PD-1 or provision of costimulation results in autoimmune vitiligo, demonstrating that LECs are significant, albeit suboptimal, antigen-presenting cells. Because LECs express numerous peripheral tissue antigens, lack of costimulation coupled to rapid high-level up-regulation of inhibitory receptors may be generally important in systemic peripheral tolerance.

Original languageEnglish (US)
Pages (from-to)4772-4782
Number of pages11
JournalBlood
Volume120
Issue number24
DOIs
StatePublished - Dec 6 2012
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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