Involvement of interleukin 2 receptors in conceptus-derived suppression of T and B cell proliferation in horses

Abstract

Summary. The mechanism by which a horse conceptus-derived immunosuppressive factor (HCS) of Mr > 100 000 inhibits lymphocyte proliferation was investigated. The factor was obtained from the culture supernatants of 20-day-old horse conceptuses; activity, identified by reduced uptake of [3H]thymidine by mitogen-stimulated lymphocytes, was greatest (P < 0\m=.\01) in cultures stimulated by mitogen from pokeweed. HCS also suppressed cell proliferation stimulated by phytohaemagglutinin (P < 0\m=.\01), but had no effect on lipopolysaccharide-stimulated cells (P > 0\m=.\05). Data from a fluorescence\x=req-\ activated cell sorter indicated that supplementation with HCS reduced the number of T cells in phytohaemagglutinin-stimulated cultures and suppressed proliferation of T and B cells in pokeweed-mitogen-stimulated cultures compared with controls. Cell proliferation was greater (P < 0\m=.\01) in cultures supplemented with HCS 24 h after stimulation than in those treated at the start of stimulation, and was even greater (P < 0\m=.\01) when cells were treated 48 h after stimulation. The removal of HCS from treated lymphocyte cultures resulted in complete recovery of cell responsiveness, and stimulated proliferation of treated cells did not differ (P > 0\m=.\05) from that of control cells. The addition of stimulated equine lymphocyte supernatant to cultures supplemented with HCS did not significantly increase (P > 0\m=.\05) cell proliferation in response to pokeweed mitogen.Addition of recombinant human interleukin 2 (rIL-2) to HCS-treated cultures did not alter the suppressive activity of HCS, although cell proliferation was greater in cultures supplemented with rIL-2 than in controls (P < 0\m=.\01). HCS inhibition of IL-2 receptor (IL-2R) function was investigated using an IL-2-dependent murine cytolytic T lymphocyte cell line; the fraction of HCS of Mr > 100 000 had no effect (P > 0\m=.\05) on proliferation of IL-2-dependent murine cytolytic T lymphocyte cells induced by rIL-2. Together, these data suggest that HCS suppresses proliferation of T lymphocytes during the early stages of cell activation by inhibiting IL-2R interaction and that this suppression interferes with interactions between T cells and B cells, thereby also indirectly inhibiting proliferation of B cells. The potent immunosuppressive capacity of HCS may be one factor responsible for inhibiting cell-mediated fetal allograft rejection during pregnancy.

Maternal Immune Responses to Trophoblast: The Contribution of the Horse to Pregnancy Immunology

“…Extracts from day 80 placenta have been shown to inhibit the proliferation of maternal lymphocytes, 64 and co‐culture of chorionic girdle trophoblasts with maternal lymphocytes caused a decrease in proliferation and a reduction in cytokine production 65,66 . Also, a >100,000 kDa molecule isolated from culture supernatants of day 20 conceptuses, termed horse conceptus‐derived immunosuppressive factor, was found to inhibit lymphocyte proliferation by inhibiting IL‐2R expression 67 . Further investigation into trophoblast‐produced immunomodulatory factors is warranted, based upon the important role they play in other species.…”

Susceptibility of Equine Chorionic Girdle Cells to Lymphokine‐Activated Killer Cell Activity

“…*^-^^ Immunosuppressive activity of the placenta has also been demonstrated in the Roth et al34 described a >30,000 kDa substance produced in culture by Day 9-20 horse embryos which was shown to suppress lymphocyte proliferation in several mitogen-stimulated blastogenesis assays, and appeared to be acting by inhibiting responses to IL-2. 35 Lea and Bolton3' found that Day 80 endometrial cup tissue extracts suppressed mixed lymphocyte responses and blastogenesis, and demonstrated that this suppression was not due to eCG. Lea et al38 recently showed that a population of the maternal leukocytes (primarily eosinophils) associated with endometrial cup tissue are positive for Transforming Growth Factor Beta-2 (TGF-P2) mRNA.…”

Detection of Soluble Receptors for Tumor Necrosis Factor, lnterleukin-2 and lnterleukin-6 in Retroplacental Serum from Normal Pregnant Women

“…However, this question awaits further investigation. Recently, it has been reported that sIL-2R may also be produced by the conceptus [24], The expression of IL-6R is limited to a small number of cells, but soluble complexes of IL-6/IL-6R can mediate the signal through a membrane glycopro tein (gp 130), which is expressed on most cells [25], Thus, the presence of sIL-6R in RPS may imply that ubiquitous tissue targets are put under the influence of IL-6-mediated effects in pregnancy. Such accessibility of IL-6 may be a prerequisite for the occurrence of a normal placental Gynecol Obstel Invest 1996;41: [1][2][3][4]development and for the establishment of an adequate hormone production [3,26].…”