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* Department of Medical Microbiology and Hygiene, University Hospital Heidelberg, Heidelberg, Germany;
Department of Internal Medicine V, Division of Rheumatology, University Hospital, Heidelberg, Heidelberg, Germany; and
Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University, Magdeburg, Magdeburg, Germany
In the past, ZAP70 was considered a T cell-specific kinase, and its aberrant expression in B-CLL cells was interpreted as a sign of malignant transformation and dedifferentiation. It was only recently that ZAP70 was detected in normal human B cells. In this study, we show that TLR9-activated B cells resemble B-cell chronic lymphocytic leukemia cells with regard to CD5, CD23, CD25, and heat shock protein 90 expression. Furthermore, stimulatory CpG and GpC DNA oligonucleotides target CD27+IgM+ and CD27–IgM+ B cells (but not IgM– B cells) and enhance ZAP70 expression predominantly in the IgM+CD27+ B cell subset. ZAP70 is induced via activation of TLR-7 or -9 in a MyD88-dependent manner, depends on protein kinase B (PKB)/mammalian target of rapamycin signaling and is rapamycin sensitive. Furthermore, ZAP70 expression levels correlate with induction of cyclin A2, prolonged B cell proliferation, and sustained induction of PKB. These events are not observed upon CD40 ligation. However, this deficit can be overcome by the expression of constitutively active PKB, given that CD40 ligation of PKB-transgenic B cells induces B cell proliferation and ZAP70 expression. These results highlight a major difference between CD40- and TLR-7/9-mediated B cell activation and suggest that ZAP70 expression levels in B cells give an estimate of the proliferative potential and the associated PKB availability.
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1 This study was supported by Deutsche Forschungsgemeinschaft Grants BO1054/2-1 to U.B. and LO 437/5-3 to H.-M.L. and M.S. I.B.-D. is supported by an Olympia Morata grant from the medical faculty of the University of Heidelberg, Germany. This study contains parts of the doctoral thesis of A.D.
2 Address correspondence and reprint requests to Dr. Isabelle Bekeredjian-Ding, Department of Medical Microbiology and Hygiene, University of Heidelberg, Im Neuenheimer Feld 324, 1.OG, D-69120 Heidelberg, Germany. E-mail address: bekeredjian-ding{at}uni-heidelberg.de
3 Abbreviations used in this paper: B-CLL, B cell chronic lymphatic leukemia; PTO, phosphorothioate-modified ODN; PKB, protein kinase B; Hsp-90, heat shock protein 90; ODN, oligodeoxynucleotide; CD2 myrPKB tg, myrPKB-transgenic; WT, wild type; 17-AAG, 17-(allylamino)-17-demethoxygeldanamycin; MFI, mean fluorescence intensity; FSC, forward light scatter; SSC, side light scatter.
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