Mechanisms of action of regulatory T cells specific for paternal antigens during pregnancy.
OBJECTIVE
To investigate whether pregnancy-induced regulatory T cells are generated specifically for paternal antigens or expanded by hormonal changes and to study regulatory T cell-related mechanisms during pregnancy.


METHODS
We used murine models of normal, abortion-prone, and pseudopregnancy to characterize regulatory T cells and hormones by methods such as flow cytometry, molecular biology techniques, and chemiluminescence. Antigen specificity was studied in experiments in which animals were vaccinated with paternal antigens or adoptively transferred with regulatory T cells. To analyze regulatory T cell-mediated mechanisms, we used neutralizing antibodies against IL-10 or TGF-beta.


RESULTS
Regulatory T cells are activated by male antigens, and minor antigens are protected by linked immunosuppression. Our data exclude the possibility that regulatory T cell expansion during pregnancy is exclusively driven by hormonal changes. An increase in systemic regulatory T cell levels in pseudopregnant females after mating with vasectomized males but not after pseudopregnancy induced mechanically confirms generation of regulatory T cells specific for paternal antigens. As for the mechanisms, neutralizing IL-10 abrogates the protective effect of regulatory T cells, whereas blockage of TGF-beta does not provide the same effect.


CONCLUSIONS
Our data confirm that regulatory T cells act in an antigen-specific manner during pregnancy and strongly suggest that IL-10 is involved in regulatory T cell-mediated protection of the fetus. These data contribute to the knowledge of the basic mechanisms regulating immune tolerance during pregnancy, a major biologic question with important medical implications.


METHODS
II.
Schumacher
Anne
A
Institute of Medical Immunology, Charité, Universitätsmedizin, Berlin, Germany.
Wafula
Paul O
PO
Bertoja
Annarosa Zambon
AZ
Sollwedel
André
A
Thuere
Catharina
C
Wollenberg
Ivonne
I
Yagita
Hideo
H
Volk
Hans-Dieter
HD
Zenclussen
Ana Claudia
AC
D000022:Abortion, Spontaneous / Q000276:immunology*; D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D004195:Disease Models, Animal; D005220:Fathers; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000276:immunology* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology* / Q000637:transplantation; D016212:Transforming Growth Factor beta
D016212:Transforming Growth Factor beta; D016753:Interleukin-10