NFAT-dependent and -independent exhaustion circuits program maternal CD8 T cell hypofunction in pregnancy

Pregnancy is a common immunization event, but the molecular mechanisms and immunological consequences provoked by pregnancy remain largely unknown. We used mouse models and human transplant registry data to reveal that pregnancy induced exhausted CD8 T cells (Preg-TEX), which associated with prolong...

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Bibliographic Details
Published in:	The Journal of experimental medicine Vol. 219; no. 1
Main Authors:	Lewis, Emma L, Xu, Rong, Beltra, Jean-Christophe, Ngiow, Shin Foong, Cohen, Jordana, Telange, Rahul, Crane, Alexander, Sawinski, Deirdre, Wherry, E John, Porrett, Paige M
Format:	Journal Article
Language:	English
Published:	United States Rockefeller University Press 03-01-2022
Subjects:	Adoptive Transfer Animals Antigens - immunology CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Chlorocebus aethiops Female Gene Expression Profiling - methods Homeodomain Proteins - genetics Homeodomain Proteins - immunology Homeodomain Proteins - metabolism Humans Kaplan-Meier Estimate Lymphocyte Activation - genetics Lymphocyte Activation - immunology Lymphocytic Choriomeningitis - immunology Lymphocytic Choriomeningitis - virology Lymphocytic choriomeningitis virus - immunology Lymphocytic choriomeningitis virus - physiology Mice Mice, Inbred C57BL Mice, Transgenic NFATC Transcription Factors - genetics NFATC Transcription Factors - immunology NFATC Transcription Factors - metabolism Pregnancy Programmed Cell Death 1 Receptor - genetics Programmed Cell Death 1 Receptor - immunology Programmed Cell Death 1 Receptor - metabolism Skin Transplantation Spleen - cytology Spleen - immunology Spleen - metabolism Tolerance Vero Cells
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Summary:	Pregnancy is a common immunization event, but the molecular mechanisms and immunological consequences provoked by pregnancy remain largely unknown. We used mouse models and human transplant registry data to reveal that pregnancy induced exhausted CD8 T cells (Preg-TEX), which associated with prolonged allograft survival. Maternal CD8 T cells shared features of exhaustion with CD8 T cells from cancer and chronic infection, including transcriptional down-regulation of ribosomal proteins and up-regulation of TOX and inhibitory receptors. Similar to other models of T cell exhaustion, NFAT-dependent elements of the exhaustion program were induced by fetal antigen in pregnancy, whereas NFAT-independent elements did not require fetal antigen. Despite using conserved molecular circuitry, Preg-TEX cells differed from TEX cells in chronic viral infection with respect to magnitude and dependency of T cell hypofunction on NFAT-independent signals. Altogether, these data reveal the molecular mechanisms and clinical consequences of maternal CD8 T cell hypofunction and identify pregnancy as a previously unappreciated context in which T cell exhaustion may occur.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 E.L. Lewis and R. Xu are co-first authors. Disclosures: J. Cohen reported grants from National Institutes of Health outside the submitted work. E.J. Wherry is consulting or is an advisor for Merck, Marengo, Janssen, Related Sciences, Synthekine and Surface Oncology. E.J. Wherry is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences. E.J. Wherry reported personal fees from Merck, Marengo, Related Sciences, Synthekine, Surface Oncology, Danger Bio, and Arsenal Bioscience outside the submitted work. In addition, E.J. Wherry has a patent to US Patent (10,370,446) on the PD-1 pathway issued. P.M. Porrett has consulted for Janssen Research & Development within the last two years. No other disclosures were reported.
ISSN:	0022-1007 1540-9538
DOI:	10.1084/jem.20201599