Human decidual stromal cells suppress cytokine secretion by allogenic CD4⁺ T cells via PD-1 ligand interactions

BACKGROUND: Although previous reports suggest an antigen-presenting function for decidual stromal cells (DSCs), the relevance of cell-to-cell communication between DSCs and T cells at the human feto-maternal interface has not been fully elucidated. Therefore, we investigated the presence and function of human DSC-expressed B7-H1 and B7-DC co-stimulatory ligands. B7-H1 and B7-DC on peripheral antigen-presenting cells (APC) typically inhibit T cell activation after binding to their corresponding receptor, programmed death-1 (PD-1). METHODS: DSCs were isolated from human term decidua. The expression of B7-H1/B7-DC and HLA-DR and their alteration following IFN-γ and/or TNF-α stimulation were assessed. DSCs with or without IFN-γ pretreatment were co-cultured with allogenic CD4+ T cells. The effect of PD-1:B7-H1/B7-DC and T cell receptor (TCR):HLA-DR interactions on T cell cytokine production was evaluated by adding blocking antibodies. RESULTS: DSCs constitutively expressed B7-H1 and B7-DC, as well as small amounts of HLA-DR. Exogenous IFN-γ and TNF-α up-regulated the B7-H1/-DC expression on DSCs, whereas HLA-DR expression was increased only by IFN-γ. IFN-γ pretreatment of DSCs stimulated T cell cytokine production through HLA-DR up-regulation. B7-H1 blockade on DSCs strongly enhanced T cell cytokine production (IFN-γ, TNF-α and IL-2), whereas B7-DC blockade had similar but more modest effects. Blockade of both B7-H1 and B7-DC resulted in additive effects. CONCLUSIONS: Our findings support the categorization of human DSCs as non-professional APCs and suggest that PD-1 ligands on DSCs, together with major histocompatibility complex class II, may play a crucial role in the regulation of decidual CD4+ T cell cytokine production. This helps to maintain a balanced cytokine milieu at the feto-maternal interface.

Duke Scholars

Author Danny J Schust Obstetrics and Gynecology, Reproductive Endocrinology & Fert ...