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

ABSTRACT: 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-? 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-? 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-? gene promoter region and decreased IFN-? production in CD8 Tm cells upon antigen-non-specific stimulation ex vivo. Moreover, IFN-? gene hypermethylation and significantly reduced IFN-? 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-?-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-? gene hypermethylation. Our findings thus provide insights into a new mechanism through which increased female sex hormone regulate CD8 Tm cell functions during pregnancy.

SUBMITTER: Yao Y

PROVIDER: S-EPMC5714395 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Yao Yushi Y Li Hui H Ding Jie J Xia Yixin Y Wang Lei L

PLoS pathogens 20171120 11

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 imm ...[more]

PMID: 29155896

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Project description:Evaluation of antigen-specific T-cell responses to viral antigens is frequently performed on IFN-? secreting cells. However, T-cells are capable of producing many more functions than just IFN-?, some of which, like Perforin, are associated with immune protection in HIV-1 disease elite controllers. We evaluated the extent of missed T-cell functions when IFN-? secretion is used as a surrogate marker for further evaluation of T-cell functions. Intracellular cytokine staining assay and flow cytometry were used to assess peripheral blood mononuclear cells (PBMCs) from 31 HIV-infected ART-naive individuals for the extent to which gated CD4+ and CD8+ IFN-? producing and non-producing T-cells also secreted IL-2, Perforin, and TNF-? functions. Similarly, the extent of missed virus-specific responses in IFN-? ELISpot assay negative T-cells from 5 HIV-1 uninfected individuals was evaluated. Cells from HIV-infected individuals were stimulated with pooled consensus group M (Con M) peptides; and those from healthy individuals were stimulated with pooled adenovirus (Ad) peptides. Overall, frequencies of virus-specific IFN-? secreting CD4+ and CD8+ cells were low. Proportions of IFN-? negative CD4+ expressing IL-2, Perforin, or TNF-? to Con M were significantly higher (5 of 7 functional profiles) than the corresponding IFN-? positive CD4+ (0 of 7) T-cell phenotype, p?=?0.02; Fisher's Exact test. Likewise, proportions of CD8+ T-cells expressing other functions were significantly higher in 4 of the 7 IFN-? negative CD8+ T-cells. Notably, newly stimulated Perforin, identified as Perforin co-expression with IL-2 or TNF-?, was significantly higher in IFN-? negative CD8+ T-cell than in the positive CD8+ T-cells. Using SEB, lower responses in IFN-? positive cells were most associated with CD4+ than CD8+ T-cells. These findings suggest that studies evaluating immunogenicity in response to HIV and Adenovirus viral antigens should not only evaluate T-cell responsiveness among IFN-? producing cells but also among those T-cells that do not express IFN-?.

Dataset Information

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

Publications

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

Similar Datasets

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