Mesenchymal Stromal Cells Suppress T-Cell-Mediated Delayed-Type Hypersensitivity via ALCAM-CD6 Interaction

Mounting evidence suggests mesenchymal stromal cells (MSCs) suppress CD4(+) T-cell activation, but whether MSCs directly regulate activation and expansion of allogeneic T cells has not been fully deciphered. Here, we identified that both human and murine MSCs constitutively express ALCAM, a cognate ligand for CD6 receptors on T cells, and investigated its immunomodulatory function using in vivo and in vitro experiments. Our controlled coculture assays demonstrated that ALCAM-CD6 pathway is critical for MSCs to exert its suppressive function on early CD4(+)CD25(-) T-cell activation. Moreover, neutralizing ALCAM or CD6 results in the abrogation of MSC-mediated suppression of T-cell expansion. Using a murine model of delayed-type hypersensitivity response to alloantigen, we show that ALCAM-silenced MSCs lose the capacity to suppress the generation of alloreactive IFN gamma-secreting T cells. Consequently, MSCs, following ALCAM knockdown, failed to prevent allosensitization and alloreactive T-cell-mediated tissue damage.

Automated summary

Mounting evidence has shown that mesenchymal stromal cells (MSCs) can suppress CD4(+) T-cell activation, but the exact role of MSCs in regulating the activation and expansion of allogeneic T cells is still unclear. In this study, we found that both human and murine MSCs express ALCAM, a ligand for CD6 receptors on T cells, and investigated its immunomodulatory function using experiments in vivo and in vitro. Our results demonstrated that the ALCAM-CD6 pathway plays a critical role in MSCs' suppressive function on early CD4(+)CD25(-) T-cell activation. Moreover, blocking ALCAM or CD6 abolished the MSC-mediated suppression of T-cell expansion. In a mouse model, MSCs with silenced ALCAM failed to suppress the generation of alloreactive IFN gamma-secreting T cells, leading to allosensitization and alloreactive T-cell-mediated tissue damage.