TH1/TH2,3 Imbalance due to Cytokine-Producing NK, γδ T and NK-γδ T Cells in Murine Pregnancy Decidua in Success or Failure of Pregnancy




Address reprint requests to David A. Clark, Department of Medicine McMaster University, Rm. 3V39, 1200 Main St. West, Hamilton, Ont., Canada L8N 3Z5.



PROBLEM: Recurrent spontaneous abortion in DBA/2-mated CBA/J mice has been attributed to the production of Th1 cytokines (tumor necrosis factor [TNF]-α and interferon [IFN]-γ) by asialoGM1+ natural killer (NK) cells and Vγ1.1δ6.3+ T cells that infiltrate decidua by day 6.5, during the peri-implantation period. Abortions can be prevented by a second population of Vγ1.1δ6.3 cells, which infiltrate on day 8.5 of gestation, and produce the Th2 cytokine interleukin (IL)-10 and Th3 cytokine transforming growth factor (TGF)-β2. In low abortion rate immunocompetent mice, most of the TGF-β2 is derived from γδ T cells. However, TGF-β2-producing cells are present in the decidua of pregnant severe combined immune deficient (SCID) mice, which lack γδ T cells.
METHODS: The cells in day 13.5 decidua of CBA×DBA/2 matings and SCID×SCID matings were identified using flow cytometry and combined surface staining for γδ and/or asialoGM1, and intracellular cytokine staining for TNF-α, IFN-γ, and TGF-β2,3.
RESULTS: TGF-β2 and TNF-α were found in asialoGM1+ NK cells in SCID mouse decidua. In CBA×DBA/2 mated mice, two major and one minor subsets of cytokine-positive cells were identified: -γδ-only T cells, double positive asialoGM1+γδ+ (NK-γδ T) cells, and a small number of asialoGM1+γδ NK-only cells. The NK-only and NK-γδ T subsets showed a greater Th1/Th2,3 pattern of intracellular staining compared with the γδ-only subset. In the CBA×DBA/2 and SCID×SCID systems, Th1/Th2,3 ratios could not predict actual observed abortion rates but did correlate with susceptibility to abortions (if exposed to an additional stimulus such as stress). The known effect of in vivo administration of anti-asialoGM1 antibody on abortion rates within groups of mice exposed to such stresses could also be predicted.
CONCLUSION: γδ+ cells in decidua (e.g. Vγ1+ cells which can recognize trophoblasts) differ based on the presence or absence of the NK marker-asialo-GM1. NK-γδ T cells may be quite important in the Th1 response in early pregnancy that predisposes to abortions in CBA×DBA/2 matings, whereas γδ T-only cells appear to be protective. In pregnant SCID mice, the TNF-α+/TGF-β2+ NK population is greatly expanded. An activating stimulus (such as stress or endotoxin) appears to be as important in triggering abortions, as is the Th1/Th2,3 ratio at the feto–maternal interface.