Soluble T cell immunoglobulin mucin domain 3 (sTim-3) in maternal sera: a potential contributor to immune regulation during pregnancy

Objective: The immune checkpoint inhibitor, membrane-bound T cell immunoglobulin mucin domain 3 (Tim-3), binds to galectin-9 (gal-9) and promotes immune tolerance during pregnancy. Soluble Tim-3 (sTim-3) competes with Tim-3 for binding to gal-9 and modulates its activity. Our objective was to evaluate the influence of sTim-3 on immune responses and outcome in pregnant women. Study design: Peripheral blood from 71 pregnant women was separated into mononuclear cell (PBMC) and plasma fractions. The PBMCs were lysed and tested for Tim-3 by ELISA. Plasma was assayed for sTim-3, gal-9, tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10) and the stress-inducible 70 kDa heat shock protein (hsp70) by enzyme-linked immunosorbent assay (ELISA). Correlations were analyzed by the Spearman rank correlation test. Results: The higher the sTim-3 level in plasma the lower was the PBMC Tim-3 concentration (p = .0135), suggesting that sTim-3 results from the release of membrane-bound Tim-3. Plasma sTim3 levels were positively correlated with levels of gal-9 (p < .0001), TNF-alpha (p = .0071) and hsp70 (p = .0144), but not with IL-10. The sTim-3 level was positively associated (p = .0276) with gestational age at delivery. There was no association between sTim-3 and gestational age at sample collection, maternal age, gravidity, parity or body mass index. Conclusion: The release of Tim-3 from membranes and sTim-3 reacting with gal-9 may increase proinflammatory immunity and the stress response. The release of sTim-3 from lymphoid cells into the circulation and its binding to gal-9 may modulate Tim-3-mediated activity and help optimize immune regulation during pregnancy.