Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-γ gene hypermethylation

PLoS Pathogens

Jie Ding¹  Yixin Xia²  Hui Li²  Lei Wang³  Yushi Yao⁴ 

[1] Department of Clinical Nutrition, General Hospital of Chinese People's Armed Police Forces, Beijing, China;Department of Hematology, Chinese PLA General Hospital, Beijing, China;Department of Obstetrics and Gynecology, General Hospital of Chinese People's Armed Police Forces, Beijing, China;McMaster Immunology Research Center, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada

关键词: Cytotoxic T cells;    Progesterone;    DNA methylation;    Pregnancy;    Mouse models;    Spleen;    T cells;    Cell staining;   

DOI  :  10.1371/journal.ppat.1006736

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Pregnant women and animals have increased susceptibility to a variety of intracellular pathogens including Listeria monocytogenes (LM), which has been associated with significantly increased level of sex hormones such as progesterone. CD8 T memory(Tm) cell-mediated antigen-non-specific IFN-γ responses are critically required in the host defense against LM. However, whether and how increased progesterone during pregnancy modulates CD8 Tm cell-mediated antigen-non-specific IFN-γ production and immune protection against LM remain poorly understood. Here we show in pregnant women that increased serum progesterone levels are associated with DNA hypermethylation of IFN-γ gene promoter region and decreased IFN-γ production in CD8 Tm cells upon antigen-non-specific stimulation ex vivo. Moreover, IFN-γ gene hypermethylation and significantly reduced IFN-γ production post LM infection in antigen-non-specific CD8 Tm cells are also observed in pregnant mice or progesterone treated non-pregnant female mice, which is a reversible phenotype following demethylation treatment. Importantly, antigen-non-specific CD8 Tm cells from progesterone treated mice have impaired anti-LM protection when adoptive transferred in either pregnant wild type mice or IFN-γ-deficient mice, and demethylation treatment rescues the adoptive protection of such CD8 Tm cells. These data demonstrate that increased progesterone impairs immune protective functions of antigen-non-specific CD8 Tm cells via inducing IFN-γ gene hypermethylation. Our findings thus provide insights into a new mechanism through which increased female sex hormone regulate CD8 Tm cell functions during pregnancy.

【 授权许可】

CC BY