New differentiation pathway for double-negative regulatory T-cells that regulates the magnitude of immune responses (87.9)

Abstract

CD4−CD8− (double-negative, DN) T-cells are capable of down-regulating the immune response. However, the origin and developmental pathway of DN T-cells are still unclear. In this study, we showed that proliferated CD4+ T-cells could convert to DN T-cells after 4–5 rounds of either allogeneic or syngeneic DC triggered proliferation, IL-2 and IL-15 enhanced the conversion. The disappearance of CD4 molecular on converted DN T-cells was a result of CD4 gene silence. Converted DN T-cells were resistant to AICD and expressed unique cell markers and gene profile. Moreover, DN T-cells retained a stable phenotype after re-stimulation. DN T-cells converted from CD4+ T-cells exerted powerful inhibition on same, but not third party, alloantigen triggered proliferation of naïve T cells. Perforin, a cytotoxic lymphocyte related cytokine, was highly expressed by DN T-cells, played a role in DN T-cell mediated suppression. Transferring of DN T-cells alone could prevent allograft rejection and the onset of autoimmune disease in vivo. This previously unknown pathway of differentiating DN regulatory T-cells represents a negative feedback mechanism of immune response. The results of using ex vivo CD4+ T-cells converted DN T-cells in transplantation and autoimmune disease models support the concept and the feasibility of potentially utilizing this novel cell-based therapy.