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

Abstract

Thymocyte development is reported to be inhibited by pregnancy, although the impact of this effect on fertility is unknown. We demonstrate, using progesterone receptor null mutant mice, that the inhibitory effects of pregnancy hormones on T cell development require the presence of functional progesterone receptor (PR). A combination of hysterectomy, thymic immunohistochemistry, and transplant studies reveals that local expression of PR in thymic stromal cells is specifically required for thymic involution to occur. These cells, under the influence of progesterone, block T cell development at the early pre-T cell (CD3 ؊ CD44 ؉ CD25 ؉ ) stage of development via a paracrine mechanism. In addition, age-related thymic involution is shown to occur 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 normal fertility. Together, these observations provide evidence for a PR-dependent paracrine mechanism that blocks very early T cell lymphopoiesis during pregnancy and is essential for normal fertility. O ne of the long-standing enigmas of reproductive biology is why the fetus is not rejected by the mother's immune system (1-3). Many explanations for this phenomenon have been proposed and tested, including the idea of paternal antigen sequestration and reduced MHC expression (4, 5), the possibility of local immune changes in the uterus (6, 7), and a potential maternal shift from Th1 to Th2 immune responses (8-10). Although each of these mechanisms appears to play some role in protection of the fetus from the maternal immune system, none has been directly shown to be required. It now appears that pregnancy may in fact have many redundant mechanisms acting both systemically and at the maternal-fetal interface to protect the fetus from the mother's immune system.One particularly interesting effect of pregnancy on the maternal immune system is a general blockade of lymphocyte development. This blockade manifests itself grossly in the form of thymic involution and bone marrow involution. Involution of the thymus, the site of T cell differentiation, has long been recognized to occur during pregnancy in a number of species including rat, mouse, and human (11-13) and may be mimicked by the administration of the female sex hormones estrogen (E) and progesterone (P), although the relative contributions of the two hormones are controversial (14,15). Although the functional importance of pregnancy-induced thymic involution remains unknown, the fact that it has been observed in all mammals that have been examined has led to the speculation that reduced or altered output of mature T cells by the thymus could be an important component of maternal immune regulation. It also has been reported that bone marrow, the site of B lymphocyte development, undergoes an involution process similar to that occurring in the thymus during pregnancy. The result is a specific block to B cell de...

T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer

“…Given that postpubertal withdrawal of androgen promotes restitution of cellular immune components in animals (38,39) raises the possibility that restrictions on immune targeting of the prostate might be eliminated on androgen withdrawal. A similar paradigm for hormonemediated down-regulation of maternal T cell-mediated immunity to protect developing fetal tissues has recently been proposed (40).…”

Reproductive tissue selective actions of progesterone receptors

“…Specifically, female mice lacking both PRs exhibit impaired sexual behavior and neuroendocrine gonadotropin regulation, anovulation, uterine dysfunction and impaired pregnancy-associated mammary gland morphogenesis (Lydon et al 1995, Mani et al 1996, Chappell et al 1999, Tibbetts et al 1999. Furthermore, studies of the PRKO mouse reveal that PRs also play an essential role in regulation of thymic involution during pregnancy (Tibbetts et al 1999) and in the cardiovascular system through regulation of endothelial and vascular smooth muscle cell proliferation and response to vascular injury (Vazquez et al 1999).…”

Natural killer cell-triggered vascular transformation: maternal care before birth?

“…13 Interestingly, lymph nodes draining a non-pregnant but not pregnant (gd3.5-7.5 were tested) mouse uNK progenitor cells, suggesting that the gestational uterus retains mobilized uNK progenitor cells. Pregnancy induces changes in lymphoid organs, inducing, for example, thymic depletion 53,54 and blockade of dendritic cell movement to uterine-draining lymph nodes. 55 Several investigators suggest that in women, as in mice, uNK cell progenitors are of mixed endometrial and peripheral origins.…”