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

PROBLEM: Recurrent spontaneous abortion in DBA/2-mated CBA/J mice has been attributed to the production of Th1 cytokines (tumor necrosis factor [TNF]-alpha and interferon [IFN]-gamma) by asialoGM1(+) natural killer (NK) cells and V gamma1.1 delta6.3(+) T cells that infiltrate decidua by day 6.5, during the peri-implantation period. Abortions can be prevented by a second population of V gamma1.1 delta6.3 cells, which infiltrate on day 8.5 of gestation, and produce the Th2 cytokine interleukin (IL)-10 and Th3 cytokine transforming growth factor (TGF)-beta2. In low abortion rate immunocompetent mice, most of the TGF-beta2 is derived from gamma delta T cells. However, TGF-beta2-producing cells are present in the decidua of pregnant severe combined immune deficient (SCID) mice, which lack gamma delta T cells. METHODS: The cells in day 13.5 decidua of CBA x DBA/2 matings and SCID x SCID matings were identified using flow cytometry and combined surface staining for gamma delta and/r asialoGM1, and intracellular cytokine staining for TNF-alpha, IFN-gamma, and TGF-beta2,3. RESULTS: TGF-beta2 and TNF-alpha were found in asialoGM1(+) NK cells in SCID mouse decidua. In CBA x DBA/2 mated mice, two major and one minor subsets of cytokine-positive cells were identified: -gamma delta -only T cells, double positive asialoGM1(+gamma delta+) (NK-gamma delta T) cells, and a small number of asialoGM1(+) gamma delta- NK-only cells. The NK-only and NK-gamma delta T subsets showed a greater Th1/Th2,3 pattern of intracellular staining compared with the gamma delta -only subset. In the CBA x DBA/2 and SCID x 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: gamma delta (+) cells in decidua (e.g. V gamma1(+) cells which can recognize trophoblasts) differ based on the presence or absence of the NK marker-asialo-GM1. NK-gamma delta T cells may be quite important in the Th1 response in early pregnancy that predisposes to abortions in CBA x DBA/2 matings, whereas gamma delta T-only cells appear to be protective. In pregnant SCID mice, the TNF-alpha (+)/TGF-beta2(+) 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 fete-maternal interface.