Gestation stage-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss.
Stimulation of CD1d-restricted semiinvariant natural killer T cells by using the CD1d ligand alpha-galactosylceramide (alphaGalCer) induces pregnancy loss in mice through an ill-defined mechanism involving TNF, IFN-gamma, and perforin. In this article, we demonstrate that during early gestation, alphaGalCer efficiently induced pregnancy loss in C57BL/6J and BALB/cJ mice in a perforin-dependent manner. In contrast, during midgestation perforin was no longer required for pregnancy loss. Concomitant with the loss of a perforin requirement at midgestation was the emergence of strain-dependent variations in susceptibility to alphaGalCer-induced pregnancy loss. Whereas pregnant C57BL/6J mice remained susceptible to alphaGalCer at midgestation, pregnant BALB/cJ mice were resistant to its effects. Pregnancy loss during midgestation was correlated with dramatically higher serum cytokine levels, including TNF and IL-2, in the susceptible C57BL/6J strain compared with the resistant BALB/cJ strain. Thus, the stage of gestation defined two distinct mechanisms of pregnancy loss: a perforin-dependent mechanism operating at early gestation and a perforin-independent, cytokine-dominated mechanism operating after midgestation.
Division of Transplantation Surgery and Immunology, Department of Surgery, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Jonathan E
JE
Boyson
Nisha
N
Nagarkatti
Leena
L
Nizam
Mark A
MA
Exley
Jack L
JL
Strominger
D000818:Animals; D018949:Antigens, CD1 / Q000032:analysis*; D055610:Antigens, CD1d; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology; D007376:Interleukin-2 / Q000097:blood; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D018949:Antigens, CD1; D055610:Antigens, CD1d; D005699:Galactosylceramides; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D054353:Perforin