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

• Type of Material: Article
• Authors: Indira Guleria, Brigham and Women's Hospital; Arezou Khosroshahi, Emory University; Mohammed Javeed Ansari, Brigham and Women's Hospital; Antje Habicht, Brigham and Women's Hospital; Miyuki Azuma, Tokyo Medical and Dental University; Hideo Yagita, Juntendo University; Randolph J. Noelle, Dartmouth College; Anthony Coyle, Millennium Pharmaceutical Inc.; Andrew L. Mellor, Medical College of Georgia; Samia J. Khoury, Brigham and Women's Hospital; Mohamed H. Sayegh, Brigham and Women's Hospital
• Language: English
• Date: 2005-07-18
• Publisher: ROCKEFELLER UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2005, The Rockefeller University Press
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20050019
• Title of Journal or Parent Work: JOURNAL OF EXPERIMENTAL MEDICINE
• Volume: 202
• Issue: 2
• Start Page: 231
• End Page: 237
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH) grants R01 AI051559 and PO1 AI56299 and Juvenile Diabetes Research Foundation Center grant on immunological tolerance in type 1 diabetes (to M.H. Sayegh), NIH grant AI058680 and National Multiple Sclerosis Society grant RG3504 (to S.J. Khoury), and American Society of Transplantation Basic Scientist Faculty grant (to I. Guleria).
• Keywords: TRYPTOPHAN CATABOLISM; REJECTION; B7-H1; CELL COSTIMULATORY PATHWAYS; EXPRESSION; TROPHOBLAST; PD-1 PATHWAY; Life Sciences & Biomedicine; ACTIVATION; PREVENTION; T-CELLS; Immunology; Medicine, Research & Experimental; Research & Experimental Medicine; Science & Technology
• Research Categories: Health Sciences, Immunology; Health Sciences, Obstetrics and Gynecology

Abstract

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-γ-producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-γ 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.