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

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. © 2017 yao et al.