Suppression of Allogeneic Immune Responses by Human TCRαβ⁺ CD4⁻ CD8⁻ Double-Negative T Cells.

Regulatory T lymphocytes play an important role in the maintenance of immune tolerance to self antigens and are involved in downregulating immune responses in autoimmunity, transplant rejection and tumor immunity. Numerous studies have demonstrated the existence of distinct T cell subsets with immunoregulatory properties. Recently, a novel subset of TCRαβ⁺ CD4⁻ CD8⁻ (double-negative, DN) T cells has been characterized to specifically suppress immune responses in both mice and humans. Here we demonstrate for the first time that human DN T cells are highly potent suppressor cells of allogeneic CD4⁺ or CD8⁺ T cell responses after priming with allogeneic antigen presenting cells (APC). A prerequisite for the immunosuppressive activity is the repetitive priming with allogeneic dendritic cells whereas stimulation with artificial APCs has no effect. Using a transwell system we could show that the suppressive activity against allogeneic immune responses, mediated by DN T cells, requires cell contact. In contrast to murine DN T cells, which eliminate effector T cells via a fas/fasL or perforin/granzyme pathway, human DN T cells suppress the proliferation of alloreactive T cells in an active manner. Taken together, our data indicate that human DN T cells possess strong immunosuppressive effects on alloreactive CD4⁺ or CD8⁺ T cells. DN T cells may serve to limit clonal expansion of alloantigen-specific T cells after allogeneic peripheral stem cell transplantation.