Cytotoxic T cell recognition of Epstein‐Barr virus‐infected B cells. I. Specificity and HLA restriction of effector cells reactivated in vitro

Abstract

The experiments show that the phenomenon of regression, seen exclusively in Epstein-Barr (EB) virus-infected cultures of mononuclear cells from EB virus antibody-positive donors, is mediated by cytotoxic T cells reactivated in vitro and specifically recognizing an EB virus-induced lymphocyte-detected membrane antigen LYDMA. Thus, effector T cells from regressing cultures kill autologous EB virus-transformed cells but not autologous pokeweed mitogen-stimulates lymphoblasts nor any of a range of EB virus genome-negative human hemopoietic cell lines (K562, HSB2, BJAB, EB4) particularly sensitive to nonspecific natural killer-like activities. Moreover, these reactivated effector cells exhibit classical HLA restriction of target cell recognition; in a survey of 14 effector cell donors, preferential lysis of the autologous virus-transformed line was a consistent feature, while the relative degree of lysis of allogeneic lines was in general directly related to the number of HLA-A and B antigens shared between effector and target cells. The pattern of reactivity shown by effector T cell preparations from any one donor was strikingly reproducible, and the results from a number of donors revealed differences between particular HLA-A and B antigens with respect to the level of EB virus-specific killing which was associated with sharing through these determinants.

A Comparison of Epstein‐barr Virus‐specific T‐cell Immunity in Rheumatoid Arthritis and Osteoarthritis Patients

“…This conclusion is based on the fact that this laboratory has been unable to detect the cytotoxic T-cell population in cultures from healthy laboratory donors which causes regression (Tosato et al, 1982). However, since the overwhelming evidence from several independent laboratories has confirmed the presence of these EBV-specific cytotoxic T-cells in cultures from normal healthy donors (Tanaka et ai., 1980;Fukukawa et ai,, 1981;Moss et al, 1981), it seems likely that the defect in late suppressor T-cells reported by Tosato et al (1981) is, as we have reported here, a reflection of an impaired EBV-specific cytotoxic T-cell response.…”

“…These memory T-cells can be reactivated in vitro, causing a complete regression in the outgrowth of autologous EBV-infected B lymphocyte cultures. An overwhelming body of evidence from this laboratory (Misko, Moss and Pope, 1980) and from other laboratories (Tanaka et al, 1980;Fukukawa et al, 1981;Moss et al, 1981) has demonstrated that this regression is precipitated by EBV-specific cytotoxic T-cells. We have also shown that this regression is strictly dependent on the initial total lymphocyte concentration, being seen most readily at high cell concentrations, and that the 'strength' of regression (and hence the level of EBV-specific T-cellmediated immunity) can be assayed and expressed as the minimal initial cell concentration required for 50% of replicate cultures to show regression (Moss etal, 1978).…”

Assessment and characterization of the cytolytic T lymphocyte response against Epstein–Barr virus in patients with non-Hodgkin’s lymphoma after autologous peripheral blood stem cell transplantation

“…11,12 This surveillance is based mainly on CD8-positive HLA-restricted memory T cells found in the peripheral blood of seropositive individuals which can be reactivated in vitro by challenge with autologous EBVinfected B cells. [13][14][15][16][17] In immunosuppressed individuals, reactivation of this latent EBV infection can lead to the outgrowth of EBV-transformed B lymphocytes with unregulated polyclonal or monoclonal lymphoproliferation, of which the latter has a rapidly progressive and uniformly fatal course. 18,19 For this reason, the EBV-directed CTL response has been carefully investigated after allogeneic BMT, where up to 30% of the recipients of allografts from mismatched or matched unrelated donors may develop EBV lymphoma.…”

“…Although blocking experiments were not undertaken in all patients investigated, the data obtained showed the same characteristics for the EBV-specific CTL response as reported for healthy individuals. [13][14][15] It can be substantially blocked by antibodies directed against CD3 or CD8, while anti-CD4 or anti-MHC class II show no effect, and the main effector cells are CD8-positive CTLs. MHC class I restriction is further underlined by experiments using EBNA-derived nonapeptides presented by autologous PHA blasts, which demonstrated that the EBV-directed CTLs recognize only the peptide known to be associated with HLA-B8 (therefore matching the patients HLA-haplotype), whereas another, HLA-A11-restricted EBV-peptide did not lead to a significant lysis.…”

Characterisation of Epstein-Barr virus-specific memory T cells from the peripheral blood of seropositive individuals

“…In this work we have studied the generation of Ia+ T cells in cultures one week after EBV-infection of PBMC when cytotoxic T cells are known to be present (Moss et al, 1981). We have compared this with the generation of Ta + cells in identical cultures containing CSA-a drug which is known to prevent the generation of cytotoxic T cells and the regression phenomenon (Bird et al, 1981).…”