The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published 18 July 2005. doi:10.1084/jem.20050019
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 2, 231-237
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BRIEF DEFINITIVE REPORT

 A critical role for the programmed death ligand 1 in fetomaternal tolerance

Indira Guleria1, Arezou Khosroshahi1, Mohammed Javeed Ansari1, Antje Habicht1, Miyuki Azuma3, Hideo Yagita4, Randolph J. Noelle5, Anthony Coyle6, Andrew L. Mellor7, Samia J. Khoury2, and Mohamed H. Sayegh1

1 Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115
2 Center for Neurologic Diseases, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115
3 Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo 113-8549, Japan
4 Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
5 Dartmouth College, Hanover, NH 03755
6 Millennium Pharmaceutical Inc., Cambridge, MA 02139
7 Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Department of Medicine, Medical College of Georgia, Augusta, GA 309012

CORRESPONDENCE Indira Guleria: indira.guleria{at}tch.harvard.edu

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.


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