Intrinsic impairment of CD4+CD25+ regulatory T cells in acquired aplastic anemia

• Published in: Blood 2012-08, Vol.120 (8), p.1624-1632
• Main Authors: Shi, Jun, Ge, Meili, Lu, Shihong, Li, Xingxin, Shao, Yingqi, Huang, Jinbo, Huang, Zhendong, Zhang, Jing, Nie, Neng, Zheng, Yizhou
• Format: Article
• Language: English
• Subjects: Adult; Anemia, Aplastic - genetics; Anemia, Aplastic - immunology; Anemia, Aplastic - pathology; Biological and medical sciences; Bone Marrow - immunology; Bone Marrow - pathology; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Movement; Female; Gene Expression Regulation; Hematologic and hematopoietic diseases; Hematopoiesis; Humans; Immunosuppression; Interferon-gamma - immunology; Interleukin-2 Receptor alpha Subunit - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Other diseases. Hematologic involvement in other diseases; Receptors, CXCR - genetics; Receptors, CXCR4 - genetics; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Th1 Cells - immunology; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-11-390708

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.