Accumulating evidence has demonstrated that regulatory T(Treg) cells play an important role in themaintenance of immunologic self-tolerance and in down-regulating various immune responses.Thus,there hasrecently been an increasing interest in studying the biology of Treg cells as well as their potential application intreating immune diseases.Many types of Treg cell subsets have been reported in a variety of disease models.Among these subsets,αβTCR~+CD3~+CD4~-CD8~- double negative(DN) Treg cells are defined by their capability ofinhibiting immune responses via directly killing effector T cells in an antigen specific fashion.Furthermore,DNTreg cells have been shown to develop regulatory activity after encountering specific antigens,partiallymediated by the acquisition of MHC-peptide complexes from antigen presenting cells(APCs).The presentationof acquired alloantigens on DN T cells allows for the specific interaction between DN Treg cells and alloantigenreactive effector T cells.Once the DN Treg and target cells have come into contact,killing is then mediated byFas/Fas-ligand interactions,and perhaps through other unidentified pathways.Further characterization of thefunctions,molecular expression and mechanisms of activation of DN Treg cells will help in the development ofnovel therapies to induce antigen specific tolerance to self and foreign antigens.Cellular & MolecularImmunology.2004;1(5):328-335. Accumulating evidence has been demonstrated that regulatory T (Treg) cells play an important role in the maintenance of immunologic self-tolerance and in down-regulating various immune responses. It has therecently been an interest in studying the biology of Treg cells as well as their potential application intreating immune diseases.Many types of Treg cell subsets have been reported in a variety of disease models. Among these subsets, αβTCR ~ + CD3 ~ + CD4 ~ -CD8 ~ - double negative (DN) Treg cells are defined by their capability of inhibition of immune responses via directly killing effector T cells in an antigen specific fashion. Frthermore, DNTreg cells have been shown to develop regulatory activity after encountering specific antigens, partiallymediated by the acquisition of MHC-peptide complexes from antigen presenting cells (APCs). The presentationof Acquired alloantigens on DN T cells allows for the specific interaction between DN Treg cells and alloantigen reactive effector T cells. On th e DN Treg and target cells have come into contact, killing is then mediated by Fas / Fas-ligand interactions, and perhaps through other unidentified pathways. Further characterization of the activities, molecular expression and mechanisms of activation of DN Treg cells will help in the development of novel therapies to induce antigen specific tolerance to self and foreign antigens. Cellular & Molecular Immunology. 2004; 1 (5): 328-335.