High-resolution Analysis of T Cell Functions in Pregnancy

t-SNE representation of CLUSTER properties

The developing fetus needs to be protected against two types of potential immune attack:  first, inflammatory responses against pathogens can indirectly damage the placenta; and second, the immune system could potentially attack paternal antigens on fetal cells.  A wide range of overlapping protective mechanisms, in aggregate, are so effective that pregnancies with wider MHC disparity actually have a slight advantage over less-disparate pregnancies.

t-SNE representation of SUBJECT/SAMPLE properties

Non-antigen-specific damage to the placenta can be caused by excessive inflammatory responses against pathogens, particularly in responses with a strong IFNg/Th1 component.  We proposed several years ago that pregnancy may represent a Th2-skewed environment – this is probably better-formulated as a selective reduction of Th1 responses, without necessarily a skewing towards Th2 responses.  We showed in mice that Th1-biased responses were deleterious for pregnancy, and partially suppressed during pregnancy. 

Kinetics and markers of individual clusters after vaccination of pregnant or non-pregnant women

Our current model for modifications to human immune responses during pregnancy suggests that inflammatory responses should be transiently suppressed during pregnancy to protect the fetus, but that the memory responses should not be altered because it is not possible to predict whether the mother will be pregnant or not during the next exposure to the pathogen.  We conducted a clinical study of immunization with influenza vaccine during pregnancy, and showed, in support of the model, a transient alteration in the anti-influenza response seven days after vaccination, compared to non-pregnant controls.  However, the pregnant and non-pregnant responses were much more similar in samples taken before or after this time.

Current goals are to work with the ECHO study (Environmental influences on Child Health Outcomes) to analyze both anti-paternal and anti-vaccine responses using our high-resolution flow cytometry tools.  Microchimerism (fetal cells in the maternal circulation) will also be measured, and the results will all be integrated into the ECHO study.

References

• Krishnan L, Guilbert LJ, Russell AS, Wegmann TG, Mosmann TR, Belosevic M. Pregnancy impairs resistance of C57BL/6 mice to Leishmania major infection and causes decreased antigen-specific IFN-gamma response and increased production of T helper 2 cytokines. J Immunol. 1996;156(2):644-52. PMID: 8543816.
• Krishnan L, Guilbert LJ, Wegmann TG, Belosevic M, Mosmann TR. T helper 1 response against Leishmania major in pregnant C57BL/6 mice increases implantation failure and fetal resorptions. Correlation with increased IFN-gamma and TNF and reduced IL-10 production by placental cells. J Immunol. 1996;156(2):653-62. PMID: 8543817.
• Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG. Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol. 1993;151(9):4562-73. PMID: 8409418.
• Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993;14(7):353-6. PMID: 8363725.
• Seavey MM, Mosmann TR. Estradiol-induced vaginal mucus inhibits antigen penetration and CD8(+) T cell priming in response to intravaginal immunization. Vaccine. 2009;27(17):2342-9. PMID: 19428849.
• Seavey MM, Mosmann TR. Paternal antigen-bearing cells transferred during insemination do not stimulate anti-paternal CD8+ T cells: role of estradiol in locally inhibiting CD8+ T cell responses. J Immunol. 2006;177(11):7567-78. PMID: 17114426.