A critical role for the programmed death ligand 1 in fetomaternal tolerance.
Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell- but not B cell-dependent because PDL1-specific antibody treatment caused fetal rejection in B cell-deficient but not in RAG-1-deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-gamma-producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-gamma levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.
Guleria
Indira
I
Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. indira.guleria@tch.harvard.edu
Khosroshahi
Arezou
A
Ansari
Mohammed Javeed
MJ
Habicht
Antje
A
Azuma
Miyuki
M
Yagita
Hideo
H
Noelle
Randolph J
RJ
Coyle
Anthony
A
Mellor
Andrew L
AL
Khoury
Samia J
SJ
Sayegh
Mohamed H
MH
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D060890:B7-H1 Antigen; D005260:Female; D005327:Fetal Resorption / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007371:Interferon-gamma / Q000276:immunology; D008431:Maternal-Fetal Exchange / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D011247:Pregnancy; D018417:Th1 Cells / Q000276:immunology
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D010455:Peptides; C064658:RAG-1 protein; D007371:Interferon-gamma