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

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.