Up-regulation of NKG2A inhibitory receptor on circulating NK cells contributes to transfusion-induced immunodepression in patients with β-thalassemia major

Abstract

Accumulating evidence has shown that allogeneic blood transfusions can induce significant immunosuppression in recipients, and thereby increase the risk of postoperative infection and/or tumor relapse. Although it is well known that natural killer (NK) cells are responsible for the immunodepression effects of transfusion, the underlying mechanisms remain obscure. In this study, we investigated the role of NK cells in transfusion-induced immunodepression in β-thalassemia major. The proportion of circulating NK cells and the expression of NK receptors (NKG2A, CD158a, NKP30, NKP46 and NKG2D) as well as CD107a were detected by multicolor flow cytometry. IFN-γ production by circulating NK cells was detected by intracellular cytokine staining. Our results showed that the proportion and cytotoxicity (CD107a expression) of circulating NK cells in transfusion-dependent β-thalassemia major patients were remarkably lower than those of β-thalassemia minor patients or healthy volunteers. Expression of NKG2A inhibitory receptor on circulating NK cells in patients with β-thalassemia major was remarkably up-regulated, but there were no significant differences in the expression levels of NKP30, NKP46, NKG2D, CD158a and IFN-_γ. These results indicate NKG2A inhibitory receptor may play a key role in transfusion-induced immunodepression of NK cells in patients with β-thalassemia major.

Keywords

natural killer cells / NKG2A / thalassemia / transfusion / immunodepression

References

[1] JensenLS, AndersenAJ, ChristiansenPM, et al. . Postoperative infection and natural killer cell function following blood transfusion in patients undergoing elective colorectal surgery. Br J Surg, 1992, 79(6): 513-516 PMID: 1611441

[2] HeissMM, Fasol-MertenK, AllgayerH, et al. . Influence of autologous blood transfusion on natural killer and lymphokine-activated killer cell activities in cancer surgery. Vox Sang, 1997, 73(4): 237-245 PMID: 9407641

[3] GhioM, ContiniP, NegriniS, et al. . Down regulation of human natural killer cell-mediated cytolysis induced by blood transfusion: role of transforming growth factor-β(1), soluble Fas ligand, and soluble Class I human leukocyte antigen. Transfusion, 2011, 51(7): 1567-1573 PMID: 21214580

[4] LanierLL. NK cell recognition. Annu Rev Immunol, 2005, 23: 225-274 PMID: 15771571

[5] ChenW, ZhangX, ShangX, et al. . The molecular basis of beta-thalassemia intermedia in southern China: genotypic heterogeneity and phenotypic diversity. BMC Med Genet, 2010, 11: 31 PMID: 20181291 PMCID: 2845123

[6] XuXM, ZhouYQ, LuoGX, et al. . The prevalence and spectrum of alpha and beta thalassaemia in Guangdong Province: implications for the future health burden and population screening. J Clin Pathol, 2004, 57(5): 517-522 PMID: 15113860 PMCID: 1770296

[7] CaiR, LiL, LiangX, et al. . Prevalence survey and molecular characterization of alpha and beta thalassemia in Liuzhou city of Guangxi. Zhonghua Liu Xing Bing Xue Za Zhi (Chinese), 2002, 23(4): 281-285

[8] VamvakasEC, BlajchmanMA. Transfusion-related immunomodulation (TRIM): an update. Blood Rev, 2007, 21(6): 327-348 PMID: 17804128

[9] BlumbergN, HealJM. Immunomodulation by blood transfusions: an evolving scientific and clinical challenge. Am J Med, 1996, 101(3): 299-308 PMID: 8873492

[10] BlajchmanMA. Allogeneic blood transfusions, immunomodulation, and postoperative bacterial infection: do we have the answers yet?. Transfusion, 1997, 37(2): 121-125 PMID: 9051084

[11] HillGE, FrawleyWH, GriffithKE, et al. . Allogeneic blood transfusion increases the risk of postoperative bacterial infection: a meta-analysis. J Trauma, 2003, 54(5): 908-914 PMID: 12777903

[12] WangSC, LinKH, ChernJP, et al. . Severe bacterial infection in transfusion-dependent patients with thalassemia major. Clin Infect Dis, 2003, 37(7): 984-988 PMID: 13130412

[13] BuschOR, HopW H, van PapendrechtMA, et al. . Blood transfusions and prognosis in colorectal cancer. N Engl J Med, 1993, 328(19): 1372-1376 PMID: 8292113

[14] HarlaarJJ, GosselinkMP, HopWC, et al. . Blood transfusions and prognosis in colorectal cancer: long-term results of a randomized controlled trial. Ann Surg, 2012, 256(5): 681-687 PMID: 23095610

[15] HjalgrimH, EdgrenG, RostgaardK, et al. . Cancer incidence in blood transfusion recipients. J Natl Cancer Inst, 2007, 99(24): 1864 PMID: 18073377

[16] BrooksAG, BorregoF, PoschPE, et al. . Specific recognition of HLA-E, but not classical, HLA class I molecules by soluble CD94/NKG2A and NK cells. J Immunol, 1999, 162(1): 305-313 PMID: 9886400

[17] LiF, WeiH, WeiH, et al. . Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice gastroenterology. Gastroenterology, 2013, 144(2): 392-401 PMID: 23103614

[18] SheuBC, ChiouSH, LinHH, et al. . Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD⁸⁺ T lymphocytes in human cervical carcinoma. Cancer Res, 2005, 65(7): 2921-2929 PMID: 15805295

[19] LeavenworthJW, WangX, WenanderCS, et al. . Mobilization of natural killer cells inhibits development of collagen-induced arthritis. Proc Natl Acad Sci U S A, 2011, 108(35): 14584-14589 PMID: 21873193 PMCID: 3167502

[20] BryanCF, LeechSH, BozelkaB. The immunoregulatory nature of iron. II. Lymphocyte surface marker expression. J Leukoc Biol, 1986, 40(5): 589-600 PMID: 3095475

[21] MatznerY, KonijnAM, ShlomaiZ, et al. . Differential effect of isolated placental isoferritins on in vitro T-lymphocyte function. Br J Haematol, 1985, 59(3): 443-448 PMID: 3871631

[22] BryanCF, NishiyaK, PollackMS, et al. . Differential inhibition of the MLR by iron: association with HLA phenotype. Immunogenetics, 1981, 12(1-2): 129-140 PMID: 6451576

[23] NishiyaK, HorwitzDA. Contrasting effects of lacto ferrin on human lymphocyte and monocyte natural killer activity. J Immunol, 1982, 129(6): 2519-2523 PMID: 7142699

[24] BainesMG, LafleurFL, HolbeinBE. Involvement of transferrin and transferrin receptors in human natural killer effector:target interaction. Immunol Lett, 1983, 7(1): 51-55 PMID: 6315573