Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility

Thymocyte development is reported to be inhibited by pregnancy, although th e impact of this effect on fertility is unknown. We demonstrate, using prog esterone receptor null mutant mice, that the inhibitory effects of pregnanc y hormones on T cell development require the presence of functional progest erone receptor (PR), A combination of hysterectomy, thymic immunohistochemi stry. and transplant studies reveals that local expression of PR in thymic stromal cells is specifically required for thymic involution to occur. Thes e cells, under the influence of progesterone, block T cell development at t he early pre-T cell (CD3(-)CD44(+) CD25(+)) stage of development via a para crine mechanism. In addition, age-related thymic involution is shown to occ ur by a separate PR-independent mechanism. Finally, pregnancy studies with thymic transplants from progesterone receptor null mutant mice to wild-type female recipients demonstrate that thymic stromal PR is required for norma l fertility. Together. these observations provide evidence for a PR-depende nt paracrine mechanism that blocks very early T cell lymphopoiesis during p regnancy and is essential for normal fertility.