PD-L1 regulates the development, maintenance, and function of induced regulatory T cells

J Exp Med. 2009 Dec 21;206(13):3015-29. doi: 10.1084/jem.20090847. Epub 2009 Dec 14.

Abstract

Both the programmed death (PD) 1-PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1(-/-) antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1-coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1(-/-)PD-L2(-/-) Rag(-/-) recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-1 Antigen / physiology*
  • B7-H1 Antigen
  • Carrier Proteins / physiology
  • Forkhead Transcription Factors / physiology
  • Leukocyte Common Antigens / analysis
  • Lung / pathology
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Peptides / physiology*
  • Phosphotransferases (Alcohol Group Acceptor) / physiology
  • Programmed Cell Death 1 Ligand 2 Protein
  • Proto-Oncogene Proteins c-akt / physiology
  • Signal Transduction
  • T-Lymphocytes, Regulatory / physiology*
  • TOR Serine-Threonine Kinases
  • Transforming Growth Factor beta / physiology

Substances

  • B7-1 Antigen
  • B7-H1 Antigen
  • Carrier Proteins
  • Cd274 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Membrane Glycoproteins
  • Pdcd1lg2 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Ligand 2 Protein
  • Transforming Growth Factor beta
  • Phosphotransferases (Alcohol Group Acceptor)
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Leukocyte Common Antigens
  • Ptprc protein, mouse