Pregnancy-related factors induce immune tolerance through regulation of sCD83 release

A well-balanced maternal immune system is crucial to maintain fetal tolerance in case of infections during pregnancy. Immune adaptations include an increased secretion of soluble mediators to protect the semi-allogeneic fetus from excessive pro-inflammatory response. B lymphocytes acquire a higher capacity to express CD83 and secrete soluble CD83 (sCD83) upon exposure to bacteria-derived components such as LPS. CD83 possesses immune modulatory functions and shows a promising therapeutic potential against inflammatory conditions. The administration of sCD83 to pregnant mice reduces LPS-induced abortion rates. The increased CD83 expression by endometrial B cells as compared to peripheral blood B cells suggests its modulatory role in the fetal tolerance, especially in the context of infection. We postulate that in pregnancy, CD83 expression and release is controlled by pregnancy-related hormones. The intra- and extracellular expression of CD83 in leukocytes from peripheral blood or <i>decidua basalis</i> and <i>parietalis</i> at term were analyzed by flow cytometry. After treatment with pregnancy-related hormones and LPS, ELISA and qPCR were performed to study sCD83 release and <i>CD83</i> gene expression, respectively. Cleavage prediction analysis was used to find potential proteases targeting CD83. Expression of selected proteases was analyzed by ELISA. Higher levels of CD83 were found in CD11c⁺ dendritic cells, CD3⁺ T cells and CD19⁺ B cells from <i>decidua basalis</i> and <i>decidua parietalis</i> after LPS-stimulation <i>in vitro</i>. An increase of intracellular expression of CD83 was also detected in CD19⁺ B cells from both compartments. Stimulated B cells displayed significantly higher percentages of CD83⁺ cells than dendritic cells and T cells from <i>decidua basalis</i> and peripheral blood. Treatment of B lymphocytes with pregnancy-related molecules (E2, P4, TGF-β1 and hCG) enhanced the LPS-mediated increase of CD83 expression, while dexamethasone led to a reduction. Similarly, the release of sCD83 was increased under TGF-β1 treatment but decreased upon dexamethasone stimulation. Finally, we found that the hormonal regulation of CD83 expression is likely a result from a balance between gene transcription from <i>CD83</i> and the modulation of the metalloproteinase MMP-7. Thus, data supports and complements our previous murine studies on hormonal regulation of CD83 expression, reinforcing its immunomodulatory relevance in anti-bacterial responses during pregnancy.