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Journal of Virology, June 2005, p. 7355-7362, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7355-7362.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus LMP2A Alters In Vivo and In Vitro Models of B-Cell Anergy, but Not Deletion, in Response to Autoantigen

Michelle A. Swanson-Mungerson, Robert G. Caldwell, Rebecca Bultema, and Richard Longnecker*

Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Received 17 September 2004/ Accepted 2 February 2005

A significant percentage of the population latently harbors Epstein-Barr virus (EBV) in B cells. One EBV-encoded protein, latent membrane protein 2A (LMP2A), is expressed in tissue culture models of EBV latent infection, in human infections, and in many of the EBV-associated proliferative disorders. LMP2A constitutively activates proteins involved in the B-cell receptor (BCR) signal transduction cascade and inhibits the antigen-induced activation of these proteins. In the present study, we investigated whether LMP2A alters B-cell receptor signaling in primary B cells in vivo and in vitro. LMP2A does not inhibit antigen-induced tolerance in response to strong stimuli in an in vivo tolerance model in which B cells are reactive to self-antigen. In contrast, LMP2A bypasses anergy induction in response to low levels of soluble hen egg lysozyme (HEL) both in vivo and in vitro as determined by the ability of LMP2A-expressing HEL-specific B cells to proliferate and induce NF-{kappa}B nuclear translocation after exposure to low levels of antigen. Furthermore, LMP2A induces NF-{kappa}B nuclear translocation independent of BCR cross-linking. Since NF-{kappa}B is required to bypass tolerance induction, this LMP2A-dependent NF-{kappa}B activation may complete the tolerogenic signal induced by low levels of soluble HEL. Overall, the findings suggest that LMP2A may not inhibit BCR-induced signals under all conditions as previously suggested by studies with EBV immortalized B cells.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Ward 6-231, 303 E. Chicago Avenue, Chicago, IL 60611. Phone: (312) 503-0467. Fax: (312) 503-1339. E-mail: r-longnecker{at}northwestern.edu.

Journal of Virology, June 2005, p. 7355-7362, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7355-7362.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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