Abstract
Exosome release by viable cells is a feature of activated cell types, including tumors, fetal cells, and cells of the immune system. Exosomes critically regulate immune activation, by mediating activation-induced cell death. Fetal cells may mimic these events to selectively delete reactive lymphocytes. In this study the presence and composition of placenta-derived exosomes are demonstrated in the maternal circulation along with their consequences on T cell activation markers. For all pregnant patients, exosomes were isolated from sera obtained between 28 and 30 wk gestation. For pregnant women, subsequently delivering at term, circulating levels of placental exosomes were 1.8 times greater than those delivering preterm (p < 0.0001). Exosomes isolated from pregnancies subsequently delivering at term expressed significantly higher levels of biologically active components, including Fas ligand (FasL) and HLA-DR, than those from pregnancies delivering preterm. Standardizing for protein concentrations, exosomes from term-delivering pregnancies exhibited greater suppression of CD3-zeta and JAK3 than those delivering preterm. The suppression of CD3-zeta and JAK3 correlated with exosome expression levels of FasL (r2= 0.92 and r2= 0.938, respectively). Fractionation of exosomes from term-delivering pregnancies by continuously eluting electrophoresis indicated that intact 42 kD FasL and an unidentified 24-kDa protein were associated with CD3-zeta suppression. Our results demonstrated that exosomes from pregnancies ultimately delivering at term are present at significantly greater concentrations than those from pregnancies delivering preterm; however, exosomes from term-delivering pregnancies also exhibit significantly greater suppression of CD3-zeta and JAK3.
Highlights
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To determine whether exosome-associated Fas ligand (FasL) is responsible for the suppression of Jurkat T cell CD3- expression, blockage of exosome-induced effects was analyzed in these cells using anti-Fas (ZB4) Ab (Fig. 9)
Exosomes appear to play a central role in communication between lymphocytes and dendritic cells, mediating the development of cellular immune responses or suppressing excessive activation, as in activation-induced cell death (AICD) (16 –19)
Summary
The exosome modulation of CD3- expression was performed as described above, except to assess the role of FasL in mediating this effect, cultures of Jurkat cells (2 ϫ 105 cells/ml) were initially incubated with anti-Fas neutralizing mAb, ZB4 (10 g/ml), or IgG1 isotype control (10 g/ml; Upstate Biotechnology), followed by medium alone or treatment with 200 g/ml group 1 exosomes (term pregnancies; n ϭ 5) for 48 h. Because during normal pregnancy decreased production of Th1 cytokines is observed, the effects of group 1 and 2 serum-derived exosomes or the analogous material isolated from group 3 nonpregnant controls were addressed on T cell production of IL-2.
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