Expression of the cytoplasmic tail of LMP1 in mice induces hyperactivation of B lymphocytes and disordered lymphoid architecture.
The oncogenic EBV protein LMP1 mimics a dysregulated CD40 receptor in vitro. To compare CD40 and LMP1-mediated events in vivo, transgenic mice were engineered to express mouse CD40 (mCD40tg) or a protein with extracellular mCD40 and cytoplasmic LMP1 (mCD40-LMP1tg). Transgenic and CD40(-/-) mice were bred so that only the transgenic CD40 molecule is expressed in B cells, macrophages, and dendritic cells. mCD40-LMP1tg mice had normal lymphocyte subsets, and immunization elicited an antibody response featuring normal isotype switching, affinity maturation, and germinal center (GC) formation. However, unimmunized mCD40-LMP1tg mice had expanded immature and germinal center B cells, produced autoantibodies, exhibited marked splenomegaly and lymphadenopathy, and elevated serum IL-6. Thus, signaling through the LMP1 cytoplasmic tail results in amplified and abnormal mimicry of CD40 functions in vivo, indicating possible ways in which LMP1 contributes to the pathogenesis of EBV-associated human disease.
Department of Microbiology, Univeristy of Iowa, Iowa City, Iowa 52242, USA.
Laura L
LL
Stunz
Lisa K
LK
Busch
Melissa E
ME
Munroe
Curt D
CD
Sigmund
Lorraine T
LT
Tygrett
Thomas J
TJ
Waldschmidt
Gail A
GA
Bishop
D000818:Animals; D000917:Antibody Formation; D015551:Autoimmunity / Q000276:immunology / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000209:etiology / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism*; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000276:immunology / Q000378:metabolism*
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007136:Immunoglobulins; D015850:Interleukin-6; D014763:Viral Matrix Proteins