A potential tolerogenic immune mechanism by trophoblast cells through the activation of chemokine-induced T cell death and regulatory T cell modulation

L. FRACCAROLI; J. ALFIERI; M. CALAFAT; L. LAROCCA; G. MOR; C. PEREZ LEIROS; R. RAMHORST

HUMAN REPRODUCTION

ESHRE

Lugar: Oxford; Año: 2009 vol. 24 p. 166 - 175

0268-1161

Background: Successful implantation occurs followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. Since RANTES (Regulated on activated normal T cells expressed and secreted) promotes a Th1 response and is implicated as a physiologic tolerogenic factor, we studied its implication in the trophoblast-maternal leukocyte dialogue. Methods: We performed co cultures of immortalized trophoblast cell line (Swan 71) and Peripheral Blood Mononuclear cells (PBMCs) from fertile women or with recurrent spontaneous abortions (RSA). After 24 and 48 hours of culture supernatant and cells were recovered for ELISA, FACS analysis, Western blots and apoptosis assays. To investigate physiological effects at peripheral level, we performed co cultures with maternal and paternal PBMCs with condition media from Swan cells and progesterone. Results: Following the interaction of maternal PBMCs and trophoblast cells, RANTES production increased and was accompanied by low levels of IFNg, IL-12 p70 and high levels of TNFa, nitrites and LIF expression. RANTES production resulted in elevated apoptosis of potential deleterious maternal CD3+ lymphocytes correlating with a decrease in the proliferative maternal -response. During fetal-maternal dialogue, the anti-RANTES Ab significantly reduced the frequency of CD4+CD25+Foxp3+ cells and was associated with trophoblast cell survival. However, co cultures of Swan cells and RSA-PBMCs displayed a differential RANTES kinetics, lower levels of Tregs and CD3+Annexin-V+ cells correlating with higher levels of apoptotic throphoblast cells. Conclusions: RANTES promotes an adequate pro-implantatory microenvironment that influences trophoblast cell survival and modulates the balance of maternal Treg/T effector lymphocytes in favor of maternal tolerance. Key words: chemokines, recurrent spontaneous abortions, tolerance and pregnancy.