Epstein-Barr Virus (EBV) is an etiologic factor in human B lymphocyte proliferative disorders, including infectious mononucleosis, Burkitt lymphoma and malignant lymphomas of immunodeficient patients, and alters the growth of B lymphocytes in vitro. EBV-immortalized cells phenotypically resemble in vitro antigen receptor stimulated B cells, suggesting that EBV transforms cells through interactions with normal growth regulatory pathways. To investigate mechanisms of lymphocyte growth regulation and transformation, cell genes activated by EBV infection have been identified. The EBI 3 gene is induced by EBV transformation or mitogen stimulation of peripheral blood lymphocytes, and encodes a previously unknown cytokine receptor closely related to the p40 subunit of interleukin-12 (IL-12) and receptors for ciliary neurotropic factor (CNTFR) and interleukin-6 (IL-6R). EBI 3 is functionally similar to IL-12 p40 and soluble cytokine receptor isoforms in that it lacks a transmembrane domain and is secreted. EBI 3 is also present on membranes of EBV-transformed B lymphocytes. By analogy with IL-12 p40 and soluble forms of IL-6R and CNTFR, EBI 3 membrane association is probably mediated by ligand-dependent binding to an integral membrane protein. The long-term objective is to determine the function of EBI 3 in lymphocyte growth regulation and transformation by EBV.
Specific aims are to identify cells that express EBI 3 in vivo, to identify proteins that associate with EBI 3, and to characterize EBI 3 effects on B and T lymphocytes. EBI 3-producing cells will be characterized phenotypically by double immunofluorescence staining of lymphoid tissues and fixed cells using antibodies specific for EBI 3 and leukocyte differentiation markers, to correlate differentiation markers, to correlate differentiation state with EBI 3 synthesis. EBI 3- associated ligand and membrane proteins will be identified by coimmunoprecipitation from metabolically-labeled supernatants, and from surface-labeled, digitonin-solubilized membranes of EBV transformed cells, respectively. Specific EBI 3 activities on lymphocyte phenotype and growth will be determined. EBV-negative cells transfected with EBI 3 will be assessed for changes in phenotype and expression of other recently identified EBV-induced genes. The effects of EBI 3 on growth or differentiation of normal resting or mitogen activated lymphocytes will also be evaluated. The structure of EBI 3 and its expression pattern suggest this novel receptor may have important effects on EBV- infected lymphocytes, or may modulate immune responses to the virus. These studies should enhance our understanding of immune regulation in general, and of mechanisms of growth control specifically in normal and virus-transformed lymphocytes.
| Nieuwenhuis, Edward E S; Neurath, Markus F; Corazza, Nadia et al. (2002) Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice. Proc Natl Acad Sci U S A 99:16951-6 |
| Devergne, O; Hummel, M; Koeppen, H et al. (1996) A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes. J Virol 70:1143-53 |
