IL-6 trans-signaling and the frequency of CD4+FOXP3+ cells in women with reproductive failure

Arruvito, L.; Billordo, A.; Capucchio, M.; Prada, M.E.; Fainboim, L.

doi:10.1016/j.jri.2009.04.010

« Previous Next »Journal of Reproductive Immunology
Volume 82, Issue 2 , Pages 158-165, November 2009

IL-6 trans-signaling and the frequency of CD4+FOXP3+ cells in women with reproductive failure☆

L. Arruvito
- Immunogenetics Laboratory, “José de San Martín” Clinical Hospital, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
- Department of Microbiology, Parasitology and Immunology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
A. Billordo
- Immunogenetics Laboratory, “José de San Martín” Clinical Hospital, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
M. Capucchio
- Immunogenetics Laboratory, “José de San Martín” Clinical Hospital, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
M.E. Prada
- Immunogenetics Laboratory, “José de San Martín” Clinical Hospital, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
L. Fainboim
- Immunogenetics Laboratory, “José de San Martín” Clinical Hospital, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
- Department of Microbiology, Parasitology and Immunology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
- Corresponding author at: Laboratorio de Inmunogenética, Hospital de Clínicas “José de San Martín”, Facultad de Medicina, Universidad de Buenos Aires, Av. Córdoba 2351 (1120), Buenos Aires, Argentina. Tel.: +54 11 5950 8756; fax: +54 11 5950 8758.

Received 2 December 2008; received in revised form 24 March 2009; accepted 13 April 2009. published online 31 July 2009.

Abstract

Pregnancy constitutes a major challenge to the maternal immune system, as it requires tolerance of paternal alloantigen. Maternal rejection of the fetus may develop when T regulatory (Treg) cells fail to control the balance between tolerance and immunity. Increasing evidence supports the role of IL-6 trans-signaling within T cells as a key pathway for blockade of the development of adaptive Treg cells. The present study investigated whether alteration of the components of the IL-6 trans-signaling might be a mechanism associated with modified immune responses in patients experiencing recurrent spontaneous abortion (RSA). In contrast with control women, sera from RSA women induced an enhanced mixed lymphocyte reaction (MLR) against paternal PBMCs, showing increased proliferation and lack of MLR-blocking factor activity. The sera from RSA women inhibited expansion of the FOXP3+ T cell population in TCR-activated PBMCs and showed an imbalance in levels of soluble components of the IL-6 trans-signaling pathway. In comparison with fertile women, those with RSA showed significantly increased levels of soluble IL-6 receptor and IL-6, and decreased levels of soluble gp130, the trans-signaling inhibitor. Finally we found that paternal alloimmunization acts to modulate serum levels of factors involved in the IL-6 trans-signaling pathway and increases the frequency of Treg cells. Consequently, women with reproductive failure show evidence of alteration in the IL-6 trans-signaling pathway which might be associated with abnormal performance of Treg cells in mediating feto-maternal tolerance.

Abbreviations: RSA, recurrent spontaneous abortion, MLR-Bf, mixed lymphocyte reaction-blocking factors, Treg cell, regulatory T cell, FOXP3, forkhead box P3, sIL-6R, soluble IL-6 receptor, sgp130, soluble glycoprotein 130, NK, natural killer, HLA, human leukocyte antigen