VIP contribution to the decidualization program: regulatory T cell recruitment.
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 toward a tolerogenic profile. Here, we evaluated the contribution of the VIP/VPAC 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 (P4) and lipopolysaccharide (LPS) simulating the inflammatory response during implantation and human iTregs (CD4(+)CD25(+)FOXP3(+)) differentiated from naïve T cells obtained from peripheral blood mononuclear cells of fertile women. We observed that VIP and its receptor VPAC1 are constitutively expressed in HESCs and that P4 increased VIP expression. Moreover, in HESC VIP induced expression of RANTES (CCL5), one of the main chemokines involved in T cell recruitment, and this effect is enhanced by the presence of P4 and LPS. Finally, assays of the migration of iTregs toward conditioned media from HESCs revealed that endogenous VIP production induced by P4 and LPS and RANTES production were involved, as 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 recruitment of iTregs toward endometrial stromal cells by increasing RANTES expression in a P4-dependent manner.
Immunopharmacology Laboratory, School of Sciences, University of Buenos Aires and IQUIBICEN- CONICET (National Research Council of Science and Technology), Int. Guiraldes 2160, Ciudad Universitaria, Pabellón 2 Piso 4, Buenos Aires C1428EHA, Argentina School of Sciences, University of Buenos Aires, Buenos Aires, Argentina Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, Yale University, New Haven, Connecticut, USA.
Esteban
E
Grasso
Daniel
D
Paparini
Mariana
M
Agüero
Gil
G
Mor
Claudia
C
Pérez Leirós
Rosanna
R
Ramhorst
D002454:Cell Differentiation; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology; D003656:Decidua / Q000276:immunology*; D010064:Embryo Implantation; D005260:Female; D006801:Humans; D011247:Pregnancy / Q000235:genetics / Q000276:immunology*; D011374:Progesterone / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D014660:Vasoactive Intestinal Peptide / Q000276:immunology*
D018946:Chemokine CCL5; D014660:Vasoactive Intestinal Peptide; D011374:Progesterone
VIP; decidualization; early pregnancy; human endometrial stromal cells