Intrinsic impairment of CD4(+)CD25(+) regulatory T cells in acquired aplastic anemia.
Acquired aplastic anemia (AA) is an immune-mediated bone marrow (BM) failure attacked by autoreactive effector T cells and BM is the main target organ. CD4(+)CD25(+) regulatory T cells (Tregs) were believed to control development and progression of autoimmunity by suppressing autoreactive effector T cells, but little was known regarding the function of Tregs in AA. Our study demonstrated that both peripheral blood (PB) and BM had decreased frequencies of Tregs, accompanied with a reversed lower ratio of Treg frequencies between BM and PB in AA. PB Tregs in AA had impaired migratory ability because of lower CXCR4 (but not for CXCR7) expression. Interestingly, we first showed that impairment of Treg-mediated immunosuppression was intrinsic to Tregs, rather than resistance of effector T cells to suppression in AA by coculture assays and criss-cross experiments in vitro. Furthermore, Tregs in AA were less able to inhibit interferon-γ production by effector T cells. Defective immunosuppression by Tregs could contribute to impaired hematopoiesis conducted by effector T cells in vitro. Our study provided powerful evidence that impairment of Tregs played a critical role in the pathophysiology of AA. Thus, patients with AA might greatly benefit from a Treg-oriented immunosuppressive strategy.
State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, People's Republic of China.
Jun
J
Shi
Meili
M
Ge
Shihong
S
Lu
Xingxin
X
Li
Yingqi
Y
Shao
Jinbo
J
Huang
Zhendong
Z
Huang
Jing
J
Zhang
Neng
N
Nie
Yizhou
Y
Zheng
D000328:Adult; D000741:Anemia, Aplastic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement; D005260:Female; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006801:Humans; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D054387:Receptors, CXCR / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D055815:Young Adult
C501896:ACKR3 protein, human; C527276:CXCR4 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D007371:Interferon-gamma