International Journal of Hematology

, Volume 106, Issue 4, pp 490–499 | Cite as

TRAIL in CD8+ T cells from patients with severe aplastic anemia

  • Chunyan Liu
  • Mengying Zheng
  • Tian Zhang
  • Rong Fu
  • Huaquan Wang
  • Ting Wang
  • Weiwei Qi
  • Zonghong Shao
Original Article


Severe aplastic anemia (SAA) is an autoimmune disease caused mainly by activated T lymphocytes. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of TNF family, which can induce apoptosis and play a significant role in the pathogenesis of many autoimmune disorders. In this study, we sought to investigate the role of TRAIL in peripheral CD8+ T cells (CTLs) from SAA patients to clarify the autoimmune mechanisms of bone marrow failure in SAA. The expression of TRAIL and TRAIL-R2 in CTLs from SAA patients and normal controls were determined by flow cytometry, real-time PCR, and western blot. Expression of perforin and granzyme B and apoptosis in CTLs were evaluated by flow cytometry. The expression of TRAIL and TRAIL-R2 in SAA patients was significantly decreased compared with controls; however, there was no statistical difference in TRAIL mRNA expression between the two groups. TRAIL expression in CTLs was negatively correlated with the expression of perforin and granzyme B, and negatively correlated with CTLs apoptosis in SAA patients. The TRAIL pathway may be responsible for abnormal CTL activation in SAA patients. Further study of TRAIL and its receptors may elucidate the pathogenesis of SAA.


Severe aplastic anemia CTL TRAIL 



This work was supported by the National Natural Science Foundation of China (81570106, 81570111, 81400085, and 81400088), Tianjin Municipal Natural Science Foundation (14JCYBJC25400, 5JCYBJC24300, and 12JCZDJC21500), and Tianjin Science and Technology support key project plan (20140109).

Compliance with ethical standards

Conflict of interest

The authors have no competing financial interests to declare.


  1. 1.
    Yamazaki H. Acquired aplastic anemia. Rinsho Ketsueki. 2016;57(2):91–7.PubMedGoogle Scholar
  2. 2.
    Zeng Y, Katsanis E. The complex pathophysiology of acquired aplastic anaemia. Clin Exp Immunol. 2015;180(3):361–70.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Miano M, Dufour C. The diagnosis and treatment of aplastic anemia: a review. Int J Hematol. 2015;101(6):527–35.CrossRefPubMedGoogle Scholar
  4. 4.
    Zonghong S, Meifeng T, Huaquan W, Limin X, Jun W, Rong F, et al. Circulating myeloid dendritic cells are increased in individuals with severe aplastic anemia. Int J Hematol. 2011;93(2):156–62.CrossRefPubMedGoogle Scholar
  5. 5.
    Liu C, Sheng W, Fu R, Wang H, Li L, Liu H, et al. Differential expression of the proteome of myeloid dendritic cells in severe aplastic anemia. Cell Immunol. 2013;285(1–2):141–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Xing L, Liu C, Fu R, Wang H, Wang J, Liu X, et al. CD8+HLA-DR+ T cells are increased in patients with severe aplastic anemia. Mol Med Rep. 2014;10(3):1252–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Schrezenmeier H, Körper S, Höchsmann B. Aplastic anemia. Dtsch Med Wochenschr. 2014;139(49):2503–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Fulda S. Tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Adv Exp Med Biol. 2014;818:167–80.CrossRefPubMedGoogle Scholar
  9. 9.
    Bertsch U, Röder C, Kalthoff H, Trauzold A. Compartmentalization of TNF-related apoptosis-inducing ligand(TRAIL) death receptor functions: emerging role of nuclear TRAIL-R2. Cell Death Dis. 2014;28(5):e1390.CrossRefGoogle Scholar
  10. 10.
    Allen JE, El-Deiry WS. Regulation of the human TRAIL gene. Cancer Biol Ther. 2012;13(12):1143–51.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bisgin A, Terzioglu E, Aydin C, Yoldas B, Yazisiz V, Balci N, et al. TRAIL death receptor-4, decoy receptor-1 and decoy receptor-2 expression on CD8+ T cells correlate with the disease severity in patients with rheumatoid arthritis. BMC Musculoskelet Disord. 2010;11:192.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bossi F, Bernardi S, Zauli G, Secchiero P, Fabris B. TRAIL modulates the immune system and protects against the development of diabetes. J Immunol Res. 2015;2015:680749.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Xiao H, Wang S, Miao R, Kan W. TRAIL is associated with impaired regulation of CD4+CD25− T cells by regulatory T cells in patients with rheumatoid arthritis. J Clin Immunol. 2011;31:1112–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Gidvani V, Ramkissoon S, Sloand EM, Young NS. Cytokine gene polymorphisms in acquired bone marrow failure. Am J Hematol. 2007;82(8):721–4.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhu F, Qiao J, Zhong XM, Wu QY, Chen W, Yao Y, et al. Antithymocyte globulin combined with cyclosporine A down-regulates T helper 1 cells by modulating T cell immune response cDNA 7 in aplastic anemia. Med Oncol. 2015;32(7):197.CrossRefPubMedGoogle Scholar
  16. 16.
    Solomou EE, Rezvani K, Mielke S, Malide D, Keyvanfar K, Visconte V, et al. Deficient CD4+CD25+FOXP3+ T regulatory cells in acquired aplastic anemia. Blood. 2007;110(5):1603–6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lehnert C, Weiswange M, Jeremias I, Bayer C, Grunert M, Debatin KM, et al. TRAIL-receptor costimulation inhibits proximal TCR signaling and suppresses human T cell activation and proliferation. J Immunol. 2014;193(8):4021–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Mezosi E, Wang SH, Utsugi S, Bajnok L, Bretz JD, Gauger PG, et al. Interleukin-1beta and tumor necrosis factor (TNF)-alpha sensitize human thyroid epithelial cells to TNF-related apoptosis-inducing ligand-induced apoptosis through increases in procaspase-7 and bid, and the down-regulation of p44/42 mitogen-activated protein kinase activity. J Clin Endocrinol Metab. 2004;89(1):250–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Inoue N, Watanabe M, Ishido N, Kodu A, Maruoka H, Katsumata Y, et al. Involvement of genes encoding apoptosis regulatory factors (FAS, FASL, TRAIL, BCL2, TNFR1 and TNFR2) in the pathogenesis of autoimmune thyroid diseases. Hum Immunol. 2016;77(10):944–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Lamhamedi-Cherradi SE, Zheng S, Tisch RM, Chen YH. Critical roles of tumor necrosis factor-related apoptosis-inducing ligand in type 1 diabetes. Diabetes. 2003;52(9):2274–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Audo R, Daien C, Papon L, Lukas C, Vittecoq O, Hahne M, et al. Osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand as prognostic factors in rheumatoid arthritis: results from the ESPOIR cohort. Arthritis Res Ther. 2015;29(17):193.CrossRefGoogle Scholar
  22. 22.
    Tawdy MH, Abd El Nasser MM, Abd El Shafy SS, Nada MA, El Sirafy MN, Magd AH. Role of serum TRAIL level and TRAIL apoptosis gene expression in multiple sclerosis and relation to brain atrophy. J Clin Neurosci. 2014;21(9):1606–11.CrossRefPubMedGoogle Scholar
  23. 23.
    Pundt N, Peters MA, Wunrau C, Strietholt S, Fehrmann C, Neugebauer K, et al. Susceptibility of rheumatoid arthritis synovial fibroblasts to FasL- and TRAIL-induced apoptosis is cell cycle-dependent. Arthritis Res Ther. 2009;11(1):R16.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Song K, Chen Y, Göke R, Wilmen A, Seidel C, Göke A, et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med. 2000;191(7):1095–104.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Desmond R, Townsley DM, Dumitriu B, Olnes MJ, Scheinberg P, Bevans M, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123(12):1818–25.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Chunyan Liu
    • 1
  • Mengying Zheng
    • 1
  • Tian Zhang
    • 1
  • Rong Fu
    • 1
  • Huaquan Wang
    • 1
  • Ting Wang
    • 1
  • Weiwei Qi
    • 1
  • Zonghong Shao
    • 1
    • 2
  1. 1.The Department of HematologyGeneral Hospital of Tianjin Medical UniversityTianjinChina
  2. 2.The Department of HematologyThe Second Hospital of Tianjin Medical UniversityTianjinChina

Personalised recommendations