Epstein-Barr virus LMP2A alters in vivo and in vitro models of B-cell anergy, but not deletion, in response to autoantigen.
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-kappaB nuclear translocation after exposure to low levels of antigen. Furthermore, LMP2A induces NF-kappaB nuclear translocation independent of BCR cross-linking. Since NF-kappaB is required to bypass tolerance induction, this LMP2A-dependent NF-kappaB 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.
Swanson-Mungerson
Michelle A
MA
Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Ward 6-231, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
Caldwell
Robert G
RG
Bultema
Rebecca
R
Longnecker
Richard
R
D000818:Animals; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D017635:Clonal Anergy; D004854:Herpesvirus 4, Human / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D001324:Autoantigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D014763:Viral Matrix Proteins; C421864:hen egg lysozyme; D009113:Muramidase