De novo induction of platelet-specific CD4(+)CD25(+) regulatory T cells from CD4(+)CD25(-) cells in patients with idiopathic thrombocytopenic purpura.
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-beta 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.
Zhang
Xiao-Lin
XL
Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong, PR China.
Peng
Jun
J
Sun
Jian-Zhi
JZ
Liu
Jia-Jun
JJ
Guo
Cheng-Shan
CS
Wang
Zhen-Guang
ZG
Yu
Yuan
Y
Shi
Yan
Y
Qin
Ping
P
Li
Shu-Guang
SG
Zhang
Li-Ning
LN
Hou
Ming
M
D001792:Blood Platelets / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010980:Platelet Membrane Glycoproteins / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D010980:Platelet Membrane Glycoproteins; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human