Decidua-Associated Suppressor Cells in Abortion-Prone DBA/2-Mated CBA/J Mice that Release Bioactive Transforming Growth Factor β2-related Immunosuppressive Molecules Express a Bone Marrow-Derived Natural Suppressor Cell Marker and γδ8 T-Cell Receptor1

Abstract

The decidua of allopregnant mice contains a novel population of Thy1 Lyt1 CD4 CD8 asialoGM1- non-B small lymphocytic suppressor cells that release transforming growth factor (TGF) SS2-related suppressor molecules. The "null" phenotype of this cell population is similar to some bone marrow-derived natural suppressor cell (NSC) populations, and the latter may release TGF(beta)s. We now report that the TGF beta2-producing suppressor cells in the uterine decidua of DBA/2-mated CBA/J female mice-linked to prevention of abortions-are inactivated effectively by 1E5/B5.1 but not by 2C1.1 rat monoclonal antibodies to murine pregnancy-associated splenic NSC in the presence of complement. Immunostaining of a subpopulation of cells in decidua with 1E5/B5.1 but not with 2C1.1 was shown by flow cytometry. Release of suppressor factor was also abrogated by 1E5/B5.1 + complement but not by 2C1.1 + complement, and the suppressor factor was specifically neutralized by anti-TGF beta2 and not by anti-TGF beta3. Splenic pregnancy NSC are susceptible to 2C1.1, produce TGF beta1, and express CD3 and alpha beta T-cell receptor (TcR) chains. Release of suppressor factor by the decidual NSC was abrogated by treatment with anti-CD3 (145 2C11) and anti-TcR gamma delta (GL4) monoclonal antibodies + complement, but not by anti-TcR alpha beta (H57) + complement; and cells sorted using anti-TcR gamma delta (GL3) released suppressive activity in vitro. Slightly more suppressive activity was released by implantation-site decidua where there was no epithelium than from epithelialized inter-implantation-site decidua; no significant activity was released from placental tissue, but combining implantation-site tissue with placental tissue led to release of enhanced levels of immunosuppressive activity. There appear to be subtypes of bone marrow-derived TcR+ NSC with different phenotypes and tissue localization patterns in pregnancy. The previously reported dependence of decidual NSC activity on the presence of soluble signals from fetal trophoblast may be explainable by the ability of cells bearing TcR gamma delta to recognize and react to placental trophoblast cell antigen.

Developmental exposure of mice to TCDD elicits a similar uterine phenotype in adult animals as observed in women with endometriosis

“…Nevertheless, successful pregnancy, which is reliant on progesterone in either species, is also known to be dependent upon appropriate expression of decidual TGF-β2 in mice [46][47][48]. Therefore, in the current study, we further explored whether the reduced PR expression observed in adult mice uteri subsequent to in vivo TCDD exposure impacted TGF-β2 expression in response to either estradiol alone or estradiol plus progesterone.…”

Dietary <i>Echinacea purpurea</i> during Murine Pregnancy: Effect on Maternal Hemopoiesis and Fetal Growth

“…The reasons why lymphocytes are elevated in the pregnant spleen may be manifold. For example, natural suppressor cells, identifi ed as T lineage lymphocytes, during pregnancy, produce transforming growth factor ␤ 2 , a cytokine which inhibits both mono- cyte/macrophage, and NK cells, both of which are abortogenic [39][40][41][42] . Secondly, interleukin-10, another T-lineage lymphocyte product, is a powerful downregulator of infl ammatory cytokines and is associated with successful human pregnancy [43] , and is elevated in successful murine pregnancy, while absence of interleukin-10 is associated with fetal demise [43][44][45] .…”

Progesterone Inhibits Rejection of Xenogeneic Transplants in the Sheep Uterus

“…Finally, progesterone may act to inhibit graft rejection, at least in part, by inducing the presence of suppressive γδ T cells in the endometrium. This hypothesis is suggested by the fact that progesterone tended to increase the number of γδ T cells in the glandular epithelium and suppressive γδ T cells that secrete transforming-growth factor are present in the mouse uterus during pregnancy [14, 15]. In addition, there is evidence for the existence of γδ T cells that promote graft survival [24].…”

“…These three markers, one or more of which can be present on an individual lymphocyte, are: CD45R, which identifies naïve T cells; CD8, which typically represent cytotoxic T cells, and the γδ T-cell receptor, which marks a major fraction of endometrial T cells during late pregnancy in sheep [13]. Lymphocytes of the γδ T-cell lineage have been implicated as playing an immunosuppressive role during pregnancy in mice [14, 15]. …”