The normal cell cycle activation program is exploited during the infection of quiescent B lymphocytes by Epstein-Barr virus.

B lymphocytes in the peripheral circulation are maintained in a non-proliferative state. Antigen recognition stimulates limited proliferation, whereas infection with Epstein-Barr virus (EBV) results in continual proliferation and the outgrowth of immortal cell lines. Because it is not clear at which point in cell cycle the peripheral B lymphocytes are arrested, we characterized the expression of several cell cycle-associated genes in quiescent and stimulated cells. We show that the expression of four cell genes, cdc-2, cyclin E, CD23, and cyclin D2, are up-regulated approximately 100-fold as a result of EBV-mediated immortalization. Because these genes play a positive role in cell proliferation, we suggest that this regulatory switch contributes to controlling entry into the cell cycle. Transient stimulation of quiescent B lymphocytes with either a cocktail of anti-CD40, anti-IgM, and IL4, or EBV results in the rapid expression of the same four genes, suggesting that, after infection, EBV exploits the normal program of B-lymphocyte cell cycle activation.

[1]  R. Weinberg,et al.  The retinoblastoma protein and cell cycle control , 1995, Cell.

[2]  P. Farrell,et al.  [6] Methods to study epstein-barr virus and p53 status in human cells , 1995 .

[3]  G. Peters.  Stifled by inhibitions , 1994, Nature.

[4]  J. Gordon,et al.  B-cell signalling via the C-type lectins CD23 and CD72. , 1994, Immunology today.

[5]  G. Peters,et al.  EBNA‐2 and EBNA‐LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein‐Barr virus. , 1994, The EMBO journal.

[6]  Dan R. Littman,et al.  Signal transduction by lymphocyte antigen receptors , 1994, Cell.

[7]  G. Peters.  The D-type cyclins and their role in tumorigenesis , 1994, Journal of Cell Science.

[8]  G. Peters,et al.  Cyclins D1 and D2 are differentially expressed in human B-lymphoid cell lines. , 1993, Oncogene.

[9]  J. Bell,et al.  Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[10]  James M. Roberts,et al.  Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family , 1991, Cell.

[11]  E. Kieff,et al.  Early events in Epstein-Barr virus infection of human B lymphocytes. , 1991, Virology.

[12]  J. Gordon,et al.  Regulation of resting and cycling human B lymphocytes via surface IgM and the accessory molecules interleukin-4, CD23 and CD40. , 1989, Immunology.

[13]  A. Pardee.  G1 events and regulation of cell proliferation. , 1989, Science.

[14]  H. Kikutani,et al.  Two species of human Fcε receptor II ( FcεRII CD23 ): Tissue-specific and IL-4-specific regulation of gene expression , 1988, Cell.

[15]  J. Steitz,et al.  Human acidic ribosomal phosphoproteins P0, P1, and P2: analysis of cDNA clones, in vitro synthesis, and assembly , 1987, Molecular and cellular biology.

[16]  R. Bastos,et al.  Molecular structure of the gene and the 5'-flanking region of the human lymphocyte immunoglobulin E receptor. , 1987, Nucleic Acids Research.

[17]  P. Nurse,et al.  Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2 , 1987, Nature.

[18]  G. Guy,et al.  The molecules controlling B lymphocytes. , 1987, Immunology today.

[19]  T. Hirano,et al.  Molecular structure of human lymphocyte receptor for immunoglobulin E , 1986, Cell.

[20]  E. Clark,et al.  Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[21]  P. Leder,et al.  The human c-myc oncogene: Structural consequences of translocation into the igh locus in Burkitt lymphoma , 1983, Cell.

[22]  L. Stanton,et al.  Nucleotide sequence of cloned cDNA of human c-myc oncogene , 1983, Nature.