Accuri C6 Flow Cytometer System
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0305159

Received for publication March 19, 2005.
Revised April 7, 2005.
Accepted for publication May 15, 2005.

Article

Maintenance of the CD40-related immunodeficient response in hyper-IgM B cells immortalized with a LMP1-regulated mini-EBV

Kristina T. Lu *, Rebecca L. Dryer *, Charles Song {dagger}, and Lori R. Covey *@

*Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway; and {dagger}Harbor General Hospital, University of California, Los Angeles, Torrance

@ To whom correspondence should be addressed. E-mail: covey{at}biology.rutgers.edu.


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Abstract

Our previous investigation of a patient (pt1) with non-X-linked hyper-immunoglobulin M syndrome revealed a CD40-mediated defect in B cell activation that resulted in low CD23 expression and absence of germ-line transcription and class-switch recombination. These deficiencies were complemented in vitro by a high threshold of sustained signaling through CD40. To further analyze the signaling defect in pt1 B cells, two types of Epstein-Barr virus lymphoblastoid cell lines (LCLs) were generated that constitutively expressed the viral transforming protein latent membrane protein-1 (LMP1; pt1-LCL) or expressed it under the control of a tet-inducible promoter (pt1-LCLtet). As LMP1 signals through the CD40 pathway, the pt1-LCL and pt1-LCLtet lines allow comparison of downstream functions in response to constitutive LMP1 signals or regulated LMP1 and CD40 signals. Immortalized pt1-LCLs were initially CD23lo/CD38hi and reverted to a CD23hi/CD38lo phenotype upon extended growth in culture, suggesting that the CD40 defect was reversed by selection and/or constitutive expression of LMP1. In contrast, pt1-LCLtet cells retained the CD23lo/CD38hi phenotype after extended periods of culture and failed to up-regulate CD23 in response to CD40 signals. Analysis of pt1-LCLtet cells in response to the CD40 ligand in the presence or absence of LMP1-mediated signals revealed that mitogenic activation resulted only from LMP1 and not CD40 signaling, indicating a difference in the response of pt1 B cells to these two distinct signals. Together, these data demonstrate that the pt1-LCLtet cells maintain the CD40-related defect and provide a unique approach to study the independent effects of LMP1- and CD40-directed signals.

Key Words: B cell proliferation • B cell activation • lymphoblastoid • signal transduction • viral transformation




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