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* Department of Hematology, Anhui Medical University Affiliated Provincial Hospital, Hefei, China;
Departments of Immunology and Pathphysiology and Laboratory of Allergy and Clinical Immunology, Institute of Allergy and Immune-Related Diseases and Center for Medical Research, Wuhan University School of Medicine, Wuhan, China;
Department of Anatomy, Jiujiang University Medical College, Jiujiang University, Jiujiang, China;
The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China;
¶ Departments of Internal Medicine and Geriatrics, The Zongnan University Hospital, Wuhan University, Wuhan, China; and
|| Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109
Interacting with T cells, cytokine-producing B cells play a critical protective role in autoimmune diseases. However, the interaction between malignant B and T cells remains to be fully elucidated. In a previous study, we have reported that ligation of CCL19-CCR7 and CXCL13-CXCR5 activates paternally expressed gene 10 (PEG10), resulting in an enhancement of apoptotic resistance in B-cell acute lymphocytic leukemia (B-ALL) CD23+CD5+ B cells. Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell-derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells. The impairment of cytotoxicity of syngeneic CD8+ T cells is escalated by means of CCL19/CXCL13-induced up-regulation of IL-10 from B-ALL CD23+CD5+ B cells. Moreover, using a short hairpin RNA to knockdown PEG10, we provide direct evidence that increased expression of PEG10 in B-ALL CD23+CD5+ B cells is involved in malignant B-T cell interaction, contributing to the up-regulation of IL-10 expression, as well as to the impairment of cytotoxicity of syngeneic CD8+ T cells. Thus, malignant B-ALL CD23+CD5+ B cells play an immunoregulatory role in controlling different inflammatory cytokine expressions. IL-10 may be one of the critical cellular factors conferring B-ALL CD23+CD5+ B cells to escape from host immune surveillance.
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1 This work was supported by the National Natural Science Foundation of China (Grants 39870674, 30572119, 30030130, 30471509, and 30670937); Science Foundation of Anhui Province, China (Grant 98436630), and Education and Research Foundation of Anhui Province, China (Grant 98JL063) and Research Foundation from Health Department of Hubei Provincial Government, China (Grant 301140344); and a special grant from the Personnel Department of Wuhan University, China. T.J. is a Chang Jiang Scholar supported by Chang Jiang Scholars Program from Ministry of Education, People’s Republic of China and Li Ka Shing Foundation, Hong Kong, China.
2 X.W., H.Y., J.Y., T.X., Y.Y., and Y.F. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Tan Jinquan, Department of Hematology, Anhui Medical University Affiliated Provincial Hospital, Hefei, People’s Republic of China or Department of Immunology, Wuhan University School of Medicine, Wuhan University, Dong Hu Road 115, Wuchang, Wuhan, People’s Republic of China. E-mail address: jinquan_tan{at}hotmail.com
4 Abbreviations used in this paper: DC, dendritic cell; B-ALL, B cell acute lymphocytic leukemia; B-CLL, B cell chronic lymphocytic leukemia; CB, cord blood; IL10RB pAb, IL-10 receptor B polyclonal Ab; Q-PCR, quantitative RT-PCR; shRNA, short hairpin RNA.
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