Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Interleukin 10 deficiency alters the transcriptome of T regulatory cells in pregnant mice (#16)

Bihong Zhang 1 , Jelmer R Prins 2 , John E Schjenken 1 , Simon C Barry 1 , Sarah A Robertson 1
  1. Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, SA, Australia
  2. Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Maternal immune tolerance of the semi-allogeneic fetus requires CD4+FOXP3+ T regulatory (Treg) cells to suppress inflammation and anti-fetal immunity. Generation of a robust Treg cell response depends on key cytokines including interleukin 10 (IL10). Mice with a genetic deficiency in IL10 (Il10-/- mice) are susceptible to inflammation-induced fetal loss, but whether Treg cells are involved is not defined.

Female Il10-/- or C57Bl/6 (WT) mice were mated with WT males and killed at different time points during pregnancy.  The numbers and phenotypes of Treg cells in the para-aortic lymph nodes (PALN) were examined by flow cytometry. The suppressive function of CD4+CD25+ Treg cells was evaluated in mixed lymphocyte reactions. Treg cell gene expression profiles in Il10-/- and WT controls were determined by Affymetrix microarray and qPCR.

Levels of Treg cells peaked at day 9.5 post coitum with 10-fold higher numbers in KO than WT controls. In vitro, the suppressive competence of CD4+CD25+ Treg cells was unchanged in KO mice, but CD4+ T cells from Il10-/- mice showed greater loss of FOXP3 expression and increased IL17 after stimulation in vitro. Microarray and PCR results demonstrated that several genes associated with inflammation and T cell functions were upregulated in the purified PALN Treg cells of Il10-/- mice recovered in mid-gestation. In particular, the Th1 and Th17 genes Il17a, Il1r1, Il12rb and Ifng were all upregulated 2-5 fold, and Ctse encoding the cytokine-activating enzyme cathepsin E was upregulated >20-fold.

Collectively, these data indicates the pivotal role that IL10 plays in the regulation of Treg cell expansion and stability during pregnancy. We conclude that IL10 is a critical regulator of Treg cell functional competence in pregnancy and that in women, IL10 deficiency may contribute to Treg cell instability, leading to immune-associated pregnancy disorders such as preeclampsia.