Pregnancy‐induced thymic involution is associated with suppression of chemokines essential for T‐lymphoid progenitor homing

Abstract

During normal pregnancy, the thymus undergoes a severe reduction in size and thymocyte output, which may contribute to maternal-fetal tolerance. It is presently unknown whether the pregnancy-induced thymic involution also affects nonlymphoid thymic cell populations and whether these changes in stromal cells play a role in the reduction in thymocyte numbers. Here, we characterize the changes in thymic lymphoid and nonlymphoid cells and show that pregnancy results in a reduction of all major thymic lymphoid cell populations, including the early T-lymphoid progenitors (TLPs) and thymic regulatory T cells. In addition to the thymocytes, the thymic involution also includes all major nonlymphoid cell populations, which show a profound reduction in cell numbers. We also show that during pregnancy, the thymic nonlymphoid cells exhibit decreased expression of chemokines that are essential for TLP homing: CCL25, CXCL12, CCL21, and CCL19. In addition, the expression of these chemokines was substantially downregulated by shortterm treatment with progesterone but not estrogen. Collectively, these findings suggest a novel mechanism for the pregnancy-induced reduction in TLP homing and the resulting thymic involution. Keywords:Chemokines r Homing r Pregnancy r Thymus r Tolerance r T-lymphoid progenitor Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe developing fetus expresses paternal antigens and, therefore, should be rejected by the maternal immune system [1][2][3]. However, during normal pregnancy, the accompanying changes in the maternal immune system allow the semiallogenic fetus to be tolerated. Accordingly, insufficient immune modulation and a failure of tolerance induction to the developing fetus have been linked to Correspondence: Dr. Martti Laan e-mail: martti.laan@ut.ee several severe pregnancy complications, such as preeclampsia and recurrent spontaneous abortions [4][5][6].A well-documented feature of pregnancy-induced immune adaptation is the acute and transient reduction in thymus size [7,8]. This pregnancy-induced thymic involution has been found in all mammalian species examined [9] and, at least in the mouse, is required for successful implantation and normal fertility [10]. Most of the characterized mechanisms thought to underlie this * These authors contributed equally to this study.www.eji-journal.eu Eur. J. Immunol. 2016. 46: 2008-2017 Immunomodulation and immune therapies 2009 involution have been focused on pregnancy-related increases in certain steroid hormones and their effects on different thymocyte populations. For example, it has been shown that progesterone signaling is needed for thymic involution in pregnancy and this effect is related to a developmental block of thymocyte differentiation at the double negative (DN)1 stage [10]. Another study indicated that the pregnancy-induced increase in the estrogen level is responsible for diminished proliferation of virtually all thymocyte populations without affecting their a...

Qualitative Changes in Cortical Thymic Epithelial Cells Drive Postpartum Thymic Regeneration

“…We confirmed that during pregnancy, the thymus undergoes a transient involution characterized by a ∼60 and ∼80% decrease in thymic mass and cellularity, respectively, compared to nonpregnant controls (NPC, Figure 1A) (1,3). This involution is caused by a depletion of all thymocyte subsets (Figures 1B-D), due to an arrest in thymocyte proliferation and differentiation at the DN1-DN2 stage.…”

“…This involution is caused by a depletion of all thymocyte subsets (Figures 1B-D), due to an arrest in thymocyte proliferation and differentiation at the DN1-DN2 stage. This translates into an increase of DN1 proportions in the thymus ( Supplementary Figure 2A) (1,3).…”

“…That blockade in thymocyte development occurs between the DN1 and DN2 stages (CD44 + CD25 − and CD44 + CD25 + , respectively), leading to an accumulation of DN1 thymocytes during gestation (3). Pregnancy-induced thymic involution is conserved in all mammalian species examined and certainly represents a major biological challenge.…”

Development of Dog Immune System: From in Uterus to Elderly

“…Maternal thymus undergoes involution in all mammalian species examined [21], and in the mouse, at least, thymus involution is required for a successful pregnancy [22]. In this species, pregnancy-induced thymic involution is characterized by a reduction of all major thymic lymphoid and non-lymphoid cell populations [23]. Thymic cortex shrinks and medulla enlarges, increasing the number of mature thymocytes.…”

Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis

“…It is generally believed that the thymic involution that in many species occurs during pregnancy leads to decreased thymic function, proposed as a mechanism to protect the fetus from potentially harmful TH cell responses. This general "dogma" is almost exclusively based on studies in mice where thymic involution has been paralleled with decreased thymic function (Zoller et al 2007, Laan et al 2016. In contrast, there are conflicting results in humans, challenging the notion of the across-species thymic involution and function during pregnancy (Swami et al 2012).…”