Essential role for T cells in human B-cell lymphoproliferative disease development in severe combined immunodeficient mice.
Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disease (BLPD)-like lesions develop in severe combined immunodeficient (SCID) mice inoculated with peripheral blood mononuclear cells (PBMCs) from EBV-seropositive donors. We used this model to investigate the pathogenesis of EBV-associated BLPD. Tumour incidence fell from 81% to 11% when only B cells were inoculated, suggesting a key role for T cells in tumour formation. This was further underlined by the reduction in tumour incidence from 76% to 7% when PBMCs were depleted of CD4 positive (+ve) helper T cells. Tumour outgrowth was also reduced when PBMC were depleted of CD8 +ve, CD45RA +ve or CD45RO +ve T cells. The majority of PBMC-derived tumours analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) expressed mRNA for interleukin (IL) 2, 4, 6, 10 and interferon (IFN) gamma. This is the cytokine pattern seen in activated T cells and includes B-cell growth factors. In situ hybridization studies confirmed that the tumour cells themselves express the growth factors, which is consistent with autocrine-stimulated tumour growth. Our results suggest the following sequence of events: (1) T cells are essential for the initial outgrowth of tumorigenic EBV +ve B cells in vivo; (2) the neoplasm sustains its growth in an autocrine, cytokine-stimulated manner; and (3) established tumours become independent of T-cell help.
Johannessen
I
I
Department of Medical Microbiology, The University of Edinburgh Medical School, UK.
Asghar
M
M
Crawford
D H
DH
D000818:Animals; D019898:Autocrine Communication; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D006801:Humans; D017403:In Situ Hybridization; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D007376:Interleukin-2; D015850:Interleukin-6; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens