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

Emma L Lewis; Rong Xu; Jean-Christophe Beltra; Shin Foong Ngiow; Jordana Cohen; Rahul Telange; Alexander Crane; Deirdre Sawinski; E John Wherry; Paige M Porrett

doi:10.1084/jem.20201599

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

J Exp Med. 2022 Jan 3;219(1):e20201599. doi: 10.1084/jem.20201599. Epub 2021 Dec 9.

Authors

Emma L Lewis¹, Rong Xu², Jean-Christophe Beltra^{3

4

5}, Shin Foong Ngiow^{3

4

5}, Jordana Cohen⁶, Rahul Telange⁷, Alexander Crane², Deirdre Sawinski⁶, E John Wherry^{3

4

5}, Paige M Porrett^{2

4

7

8}

Affiliations

¹ Department of Obstetrics and Gynecology, The University of Pennsylvania, Philadelphia, PA.
² Department of Surgery, The University of Pennsylvania, Philadelphia, PA.
³ Department of Systems Pharmacology and Translational Therapeutics, The University of Pennsylvania, Philadelphia, PA.
⁴ Institute for Immunology, University of Pennsylvania, Philadelphia, PA.
⁵ Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA.
⁶ Department of Medicine, The University of Pennsylvania, Philadelphia, PA.
⁷ Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL.
⁸ Comprehensive Transplant Institute, The University of Alabama at Birmingham, Birmingham, AL.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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
Vero Cells

Substances

Antigens
Homeodomain Proteins
NFATC Transcription Factors
Programmed Cell Death 1 Receptor
Rhox8 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding