Paternal Antigen-Bearing Cells Transferred

Maternal immunological tolerance of the semiallogeneic fetus involves several overlapping mechanisms to balance maternal immunity and fetal development. Anti-paternal CD8 ؉ T cells are suppressed during pregnancy in some but not all mouse models. Since semen has been shown to mediate immune modulation, we tested whether exposure to paternal Ag during insemination activated or tolerized anti-paternal CD8 ؉ T cells. The uterine lumen of mated female mice contained male MHC I ؉ cells that stimulated effector, but not naive, CD8 ؉ T cells ex vivo. Maternal MHC class I ؉ myeloid cells fluxed into the uterine lumen in response to mating and cross-presented male H-Y Ag to effector, but not naive, CD8 ؉ T cells ex vivo. However, neither unprimed nor previously primed TCR-transgenic CD8 ؉ T cells specific for either paternal MHC I or H-Y Ag proliferated in vivo after mating. These T cells subsequently responded normally to i.p. challenge, implicating ignorance rather than anergy as the main reason for the lack of response. CD8 ؉ T cells responded to either peptide Ag or male cells delivered intravaginally in ovariec-tomized mice, but this response was inhibited by systemic estradiol (inducing an estrus-like state). Subcutaneous Ag induced responses in both cases. Allogeneic dendritic cells did not induce responses intravaginally even in ovariectomized mice in the absence of estradiol. These results suggest that inhibition of antiallogeneic responses is restricted both locally to the reproductive tract and temporally to the estrous phase of the menstrual cycle, potentially decreasing the risk of maternal immunization against paternal Ags during insemination. M aternal antifetal responses are regulated at several points before and during gestation (1– 4). Allogeneic paternal gene products, especially MHC class I (MHC I), 3 are expressed on the placental trophoblast (5–7). However, the issue of whether anti-paternal CD8 ϩ T cells respond to placental Ags during gestation remains controversial. In normal mice, anti-paternal CD8 ϩ T cells were neither activated nor suppressed during pregnancy (Ref. 8 and also K. unpublished observations). Results from TCR-transgenic models have been contradictory. In two studies, the numbers or functions of anti-paternal CD8 ϩ T cells were reduced during pregnancy (9, 10). These results may have been influenced by the unusual presence of extremely large numbers of anti-paternal CD8 ϩ T cells in the TCR-transgenic mice. In a third model, using either TCR-transgenic mice directly, or adoptive transfer of smaller numbers of TCR-transgenic cells to mimic a …