LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1.
The Epstein-Barr virus (EBV) protein LMP1 is considered to be a functional homologue of the CD40 receptor. However, in contrast to the latter, LMP1 is a constitutively active signaling molecule. To compare B cell-specific LMP1 and CD40 signaling in an unambiguous manner, we generated transgenic mice conditionally expressing a CD40/LMP1 fusion protein, which retained the LMP1 cytoplasmic tail but has lost the constitutive activity of LMP1 and needs to be activated by the CD40 ligand. We show that LMP1 signaling can completely substitute CD40 signaling in B cells, leading to normal B-cell development, activation, and immune responses including class-switch recombination, germinal center formation, and somatic hypermutation. In addition, the LMP1-signaling domain has a unique property in that it can induce class-switch recombination to IgG1 independent of cytokines. Thus, our data indicate that LMP1 has evolved to imitate T-helper cell function allowing activation, proliferation, and differentiation of EBV-infected B cells independent of T cells.
Rastelli
Julia
J
Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for Environment and Health, Munich, Germany.
Hömig-Hölzel
Cornelia
C
Seagal
Jane
J
Müller
Werner
W
Hermann
Andrea C
AC
Rajewsky
Klaus
K
Zimber-Strobl
Ursula
U
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D019076:Transgenes / Q000235:genetics; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007074:Immunoglobulin G; D016328:NF-kappa B; D014763:Viral Matrix Proteins; D020928:Mitogen-Activated Protein Kinases