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

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

doi:10.1084/jem.20201599

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.

Highlights

CD8 T cells provide protective immunity from pathogens, destroy tumor cells, mediate autoimmunity, and reject organ transplants (Wong and Pamer, 2003; van der Leun et al, 2020; Liblau et al, 2002; Rocha et al, 2003)
Using a mouse model in which fetal-specific maternal CD8 T cells could be identified, we found that fetal antigen drives the differentiation of hypofunctional CD8 T cells that persisted in the maternal repertoire
As polyclonal maternal T cell responses are driven by diverse tissue antigens derived from the polymorphic paternal histocompatibility complex (i.e., HLA in humans, MHC in mice), our investigations required the use of a surrogate fetal antigen that could prime maternal T cells of known specificity

Summary

Introduction

CD8 T cells provide protective immunity from pathogens, destroy tumor cells, mediate autoimmunity, and reject organ transplants (Wong and Pamer, 2003; van der Leun et al, 2020; Liblau et al, 2002; Rocha et al, 2003). As signals governing CD8 T cell differentiation may differ depending on the context of antigen encounter, it is unclear whether knowledge derived from models of infection or cancer can be generalized to CD8 T cell responses in other settings. This knowledge gap is relevant for CD8 T cell differentiation in less well– studied areas such as the maternal T cell response to the fetus, despite the fact that exposure to fetal tissue antigens during pregnancy is the most common alloimmunization event in humans (Triulzi et al, 2009)

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