An Epstein-Barr virus-associated superantigen.

Abstract

More than 90% of adults are latently infected with Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, a self-limiting lymphoproliferative disease characterized by extensive T cell activation. Reactivation of this herpesvirus during immunosuppression is often associated with oncogenesis. These considerations led us to analyze the early events that occur after exposure of the immune system to EBV. Strong major histocompatibility complex (MHC) class II- dependent but not MHC-restricted, T cell proliferation was observed in vitro in response to autologous, lytically infected EBV-transformed B cells. By measuring the appearance of the early activation marker CD69 on individual T cell V beta subsets, we could demonstrate selective activation of human V beta 13- T cells. This was confirmed with murine T cell hybridomas expressing various human BV genes. While EBV- Burkitt's lymphoma cells were nonstimulatory, they induced V beta- restricted T cell activation after EBV infection. EBV specific activation was also demonstrated in cord blood cells, excluding a recall-antigen response. Thus, all of the characteristics of a superantigen-stimulated response are seen, indicating that induction of the EBV lytic cycle is associated with the expression of a superantigen in B cells. A model is presented proposing a role for the superantigen in infection, latency, and oncogenesis.

Epstein-Barr Virus Latent Membrane Protein LMP-2A Is Sufficient for Transactivation of the Human Endogenous Retrovirus HERV-K18 Superantigen

“…HERV-K18 is a relatively recent integrant in the genome, as it is found in Old World primates but not in New World primates, indicating that it was acquired subsequent to the evolutionary divergence of these species (28). A few years ago, it was reported that Epstein-Barr virus (EBV) is associated with TCRBV13-specific superantigen activity, which is MHC class II dependent and not due to a recall antigen response (53). More recently, it was demonstrated that the superantigen activity is due to EBV transactivation of HERV-K18 env (52).…”

“…We simultaneously assessed activation of TCRBV8 T-cell hybridomas as a specificity control. Hybridoma assays were performed as described previously (52,53) by using the TCRBV13 T-cell hybridoma, hV␤13.1-1 (11,12) and the TCRBV8 T-cell hybrid YL␤8#24 (53). Figure 1A depicts the results of a representative hybridoma assay with two lymphoblastoid cell lines (LCL), Mg68 and 253.30, that were derived by transformation with EBV deletion mutants lacking the majority of the lytic genes.…”

“…Cells were washed extensively in phosphate-buffered saline, counted, and resuspended with T-cell hybrids in 96-well round-bottom plates with 10 5 antigen-presenting cells and 2 ϫ 10 4 T-cell hybrids per well. After 24 to 48 h at 37°C, the plates were frozen at Ϫ80°C to lyse the cells, and thawed supernatants were tested for the presence of IL-2 by HT-2 bioassay as previously described (53). As the positive control, the T-cell hybrids were cross-linked with plate-bound anti-CD3 (145 2C11).…”

Abnormal T Cell Receptor Signal Transduction of CD4 Th Cells in X-Linked Lymphoproliferative Syndrome

“…We hypothesize that the inability of the immune system to control EBV-infected B lymphocytes is partly due to defects in Th cell responses (15,20,37). To investigate this hypothesis, we generated continuously growing CD4 Th cells of XLP patients using herpesvirus saimiri (HVS).…”

Relative importance of CD4+ and CD8+ T cell repertoires in the development of acute graft-versus-host disease in a murine model of bone marrow transplantation

“…Incompatibility for Mtv is not particularly associated with this genetic combination since all strains of mice display a specific pattern of two to eight endogenous proviruses in their genome. 28 and cytomegalovirus 29 were shown to be associated with superantigenic responses stimulating V␤13 + and V␤12 + T cells, respectively. Interestingly, the presence of these infectious agents is known to increase the risk of GHVD in grafted patients.…”