Sema3A Mediates the Negative Regulatory Effect of Dermal Mesenchymal Stromal Cells on T Lymphocyte Responses

Abstract

Background: The inhibitory effect of dermal mesenchymal stromal cells (DMSCs) on graft versus host disease (GVHD) has been demonstrated in mice, but the underlying mechanism remains unclear. Semaphorin-3A (Sema3A) is an effective regulator in all stages of immune response. The purpose of this manuscript is to investigate the role of Sema3A in the immunosuppressive effect of human DMSCs (hDMSCs). Methods: Coculture systems of hDMSCs expressing varying levels of Sema3A and T cells were established in vitro. The effects of hDMSCs expressing different Sema3A levels on T-cell proliferation, apoptosis, cell cycle, subsets, and cytokine secretion were examined. Results: Among the hDMSC types, ov3A-hDMSCs exhibited the most significant inhibition of T-cell proliferation. si3A-hDMSCs also suppressed T-cell proliferation, albeit with noticeably weaker effects compared to ov3A-hDMSCs. Sema3A arrested T cells in the G0/G1 phase, with ov3A-hDMSCs inducing S-phase arrest in T cells more potently than si3A-hDMSCs. This effect was associated with the inhibition of cyclin dependent kinase 4 (CDK4) and cyclin D1 and the promotion of p27 expression by Sema3A secreted by hDMSCs. Further investigation revealed that Sema3A secreted by hDMSCs suppressed the phosphorylation of extracellular regulated protein kinases (ERK) and zeta-chain-associated protein of 70 kDa (ZAP70), thus influencing the expression levels of downstream factors cyclin D1 and CDK4, thereby inhibiting T-cell proliferation. Additionally, Sema3A secreted by hDMSCs promoted Th2 and Treg cell differentiation while inhibiting Th1 and Th17 differentiation, thereby impacting cytokine secretion by these cells. Conclusions: Sema3A serves as the mediator for the negative regulatory effect of hDMSCs on T lymphocyte responses.