PD-L1 regulates the development, maintenance, and function of induced regulatory T cells.
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.
Francisco
Loise M
LM
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Salinas
Victor H
VH
Brown
Keturah E
KE
Vanguri
Vijay K
VK
Freeman
Gordon J
GJ
Kuchroo
Vijay K
VK
Sharpe
Arlene H
AH
D000818:Animals; D018122:B7-1 Antigen / Q000502:physiology*; D060890:B7-H1 Antigen; D002352:Carrier Proteins / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008168:Lung / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta / Q000502:physiology
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D002352:Carrier Proteins; C498919:Cd274 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D016212:Transforming Growth Factor beta; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse