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Blood, 12 March 2009, Vol. 113, No. 11, pp. 2568-2577. Prepublished online as a Blood First Edition Paper on December 3, 2008; DOI 10.1182/blood-2008-03-148288.
PLATELETS AND THROMBOPOIESIS De novo induction of platelet-specific CD4+CD25+ regulatory T cells from CD4+CD25– cells in patients with idiopathic thrombocytopenic purpura1 Department of Hematology, Qilu Hospital, Shandong University, Jinan; 2 Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan; 3 Department of Hematology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou; 4 Department of Hematology, Second Hospital, Shandong University, Jinan; 5 Department of Science and Technology, Shandong University, Jinan; and 6 Institute of Immunology, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China
CD4+CD25+ regulatory T cells (Treg) play the critical role in maintenance of peripheral immune tolerance. However, the numbers of naturally occurring Treg (nTreg) that can be isolated from periphery are far too small to be clinically effective. The isolation and expansion of nTreg for treatment of autoimmune diseases encounter great difficulties. Whether autoantigen-specific Treg could be converted from CD4+CD25– T cells in patients with autoimmune diseases has not been reported. Here, we demonstrated that platelet glycoprotein (GP)–specific induced Treg (GP-iTreg) could be generated de novo from nonregulatory CD4+CD25–CD45RA+ cells in patients with idiopathic thrombocytopenic purpura and induced both antigen-specific and linked suppression. GP-iTreg mediated regulatory effects via modulating the T cell–stimulatory capacity of dendritic cells. By investigating the gene expression profile of iTreg-modulated dendritic cells, we provided a genome-wide assessment of the changes induced by antigen-specific iTreg and identified that the Toll-like receptor, Notch and transforming growth factor-β signaling pathways were related to the GP-specific tolerance, with the Toll-like receptor pathway being dominant. The findings in patients with idiopathic thrombocytopenic purpura will facilitate our understanding of the mechanisms of induction and maintenance of autoantigen-specific tolerance and highlight the considerable potential of antigen-specific iTreg for targeted immunotherapy in human auto-immune diseases.
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