Multiparity induces transferable-specific hypo-responsiveness or even true tolerance to either HY or paternal alloantigens.53,54

Placental products, be them placental R788 solubility dmso extracts or water-soluble material obtained from these, co-injected with alloantigenic cells, induce systemic antigen-specific LyT2+ Ts.81 These were traced in the first pregnancy in mice and in rats by Baines and Liburd. Similarly, antigen-specific MHC-restricted Ts were found in humans.82 Controversies about in vitro assays can still be traced in proceedings of the Gusberg meeting.83 In the 1980s, we studied, in detail, the in vitro properties and mode of action of these suppressor cells (specificity, mediation by a soluble factor). A part of these studies was carried out with anti I–J antisera, as many other labs working on suppression did at the time. Lee Hood’s demonstration that the I–J region does not exist while properties of the suppressor Temsirolimus in vivo factor(s) of

Gershon and Cantor were more and more improbable doomed Ts. For an excellent revision of the history of Ts, see references.84,85 We nevertheless still tested/published the role of Ts in CBA × DBA/2 matings.51 As reviewed, in,86 the CD25 and Foxp3 markers again boosted Ts on the forefront. Yet the I–J trauma lead to a more benign denomination of ‘regulatory T cells’ (Tregs), rather than ‘CD4+ Ts’, which we first saw in 1981, but termed ‘inducers’ .87 CD8+ cells are still important partners, as shown in studies by Arck, Clark and coworkers.88 Aluvihare and Darasse convincingly demonstrated that CD4+ CD25+ elimination causes foetal deaths in allopregnancy by transfer or direct in vivo experiments.89,90 Saito traced/ quantified Foxp3 cells PIK3C2G (T regs) in human decidua as well as regulatory NK/T cells.91 Robertson and coworkers92 showed that the Foxp3

marker decreases in unexplained infertility endometrial biopsies. These, and Fainbolm, detected periodic T reg modulation during the menstrual cycle, peaking in the late follicular phase.93,94 For Fainbolm, T regs from patients with RSA are ‘functionally deficient’,93 and T reg decidual recruitment correlates with expression levels of CCL3, CCL4, CCL5, CCL22, and CX3CL1.90 Finally, placenta-dependent CD8+ T regs have been demonstrated by Shao et al.,95 and this is reminiscent of earlier data in mice about LyT2 Ts.81 Could the placenta escape immune attack by resisting effector cell lysis? We have discussed the Fas/Fas ligand interaction. Membrane and soluble HLA-G (sHLA-G) also play a role, including sHLA-G secretion by the MHC-syncytiotrophoblast. Moreover, trophoblasts (and choriocarcinomas) are resistant intrinsically to cell-mediated lysis.96–98 This resistance is independent of HLA-G.99,100 The once debated soluble factors96,101,102 had properties which fits with what is now known of soluble HLA-G, be it sHLAG1/ G2 characteristics.