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Paternal Antigen-Bearing Cells Transferred during Insemination Do Not Stimulate Anti-Paternal CD8⁺ T Cells: Role of Estradiol in Locally Inhibiting CD8⁺ T Cell Responses¹

David H. Smith Center for Vaccine Biology and Immunology, and Department of Microbiology and Immunology, University of Rochester Medical Center, NY 14642

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 ovariectomized 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grant AI051869 and the Multiple Sclerosis Society Grant NS51869.

² Address correspondence and reprint requests to Dr. Tim R. Mosmann, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 609 Rochester, NY 14642. E-mail address: Tim_Mosmann{at}urmc.rochester.edu

³ Abbreviations used in this paper: MHC I, MHC class I; FRT, female reproductive tract; OVX, ovariectomized; IVAG, intravaginal; 7-AAD, 7-aminoactinomycin D; hpc, hours postcoitus; E₂, 17-estradiol; DC, dendritic cell.