VIP contribution to the decidualization program: regulatory T cell recruitment

ESTEBAN GRASSO; DANIEL PAPARINI; MARIANA AGÜERO; GIL MOR; CLAUDIA PÉREZ LEIRÓS; ROSANNA RAMHORST

JOURNAL OF ENDOCRINOLOGY

BIOSCIENTIFICA LTD

Lugar: Bristol; Año: 2014 vol. 13 p. 121 - 131

0022-0795

During early pregnancy, the human uterus undergoes profound tissue remodeling characterized by leukocyte invasion and production of proinflammatory cytokines, followed by tissue repair and tolerance maintenance induction. Vasoactive intestinal peptide (VIP) is produced by trophoblast cells and modulates the maternal immune response towards a tolerogenic profile. Here, we evaluated the VIP/VPAC system contribution to endometrial renewal, inducing decidualization and the recruitment of induced regulatory T cells (iTregs) that accompany the implantation period. For that purpose, we used an in vitro model of decidualization with a human endometrial stromal cell line (HESC) stimulated with progesterone and LPS (Lipopolysaccharide) simulating the inflammatory response during implantation and human iTregs (CD4+CD25+FOXP3+) cells differentiated from naïve T cells obtained from fertile women peripheral blood monuclear cells. We observed that VIP and its receptor VPAC1 are constitutively expressed in HESC cells and progesterone increased VIP expression. Moreover, VIP induced RANTES expression by HESC, one of the main chemokines involved in T cell-recruitment and this effect is enhanced by the presence of progesterone and LPS. Finally, migration assays of iTregs toward conditioned media from HESC cells revealed that endogenous VIP production induced by P4 and LPS and RANTES production were involved since the anti-RANTES neutralizing Ab or VIP antagonist prevented their migration. We conclude that VIP may have an active role in the decidualization process thus contributing to iTregs recruitment toward endometrial stromal cells by increasing RANTES expression in a progesterone-dependent manner.