Soluble factors produced by activated CD4⁺T cells modulate EBV latency

Abstract

Following infection with Epstein-Barr virus (EBV), the virus is carried for life in the memory B-cell compartment in a silent state (latency I/0). These cells do not resemble the proliferating lymphoblastoid cells (LCLs) (latency III) that are generated after infection. It is of fundamental significance to identify how the different EBV expression patterns are established in the latently infected cell. In view of the prompt activatability of CD4 + T cells in primary EBV infection, and their role in B-cell differentiation, we studied the involvement of CD4 + T cells in the regulation of EBV latency. Lymphoblastoid cell lines (LCLs) were cocultured with autologous or allogeneic CD4 + T cells. Activated T cells influenced the expression of two key viral proteins that determine the fate of the infected B cell. EBNA2 was down-regulated, whereas LMP1 was unregulated and the cells proliferated less. This was paralleled by the downregulation of the latency III promoter (Cp). Experiments performed in the transwell system showed that this change does not require cell contact, but it is mediated by soluble factors. Neutralizing experiments proved that the up-regulation of LMP1 is, to some extent, mediated by IL21, but this cytokine was not responsible for EBNA2 down-regulation. This effect was partly mediated by soluble CD40L. We detected similar regulatory functions of T cells in in vitro-infected lymphocyte populations. In conclusion, our results revealed an additional mechanism by which CD4 + T cells can control the EBV-induced B-cell proliferation.infectious mononucleosis | Hodgkin lymphoma F ollowing primary EBV infection, the virus is carried by its human host over a lifetime. In healthy individuals, the latent virus resides in the memory B-cell compartment (1), in cells that do not resemble the proliferating lymphoblastoid cells (LCLs) generated by in vitro infection. The carrier cells usually do not express any virally encoded proteins other than EBNA1, which is required for the maintenance of the viral episomes. They do not express the growth transformation program and have a resting phenotype and, therefore, do not represent a direct pathogenic threat.The establishment of this type of latency by EBV is a focal point of attention, ever since the virus was discovered. According to one scenario, EBV exploits the B-cell differentiation program (2). The virus infects naïve IgD + B cells that subsequently express 9 virally encoded proteins (EBNA1 through -6 and three LMPs) and transforms the cells into immunoblasts. This expression pattern is referred to as the "growth transformation," or latency III program. The key proteins of this program are EBNA2 and LMP1. Because at least six of the nine proteins are immunogenic, the proliferating immunoblasts are readily recognized and eliminated by immune effector cells. A fraction of the infected cells migrate to the lymph node follicles and concurrently change their viral transcription program to express only three proteins: EBNA1, LMP1, and LMP2 (latency II). The LMPs facili...

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