Cytotoxic effector cells specific for B Cell lines transformed by Epstein-Barr virus are present in patients with infectious mononucleosis.

Abstract

Peripheral lymphoid cells, from 12 cases of acute infectious mononucleosis (IM), were tested in a micro chromium-51 release assay for cytotoxic activity against a variety of cell lines that did or did not carry the Epstein-Barr virus (EBV) genome. Unfractionated lymphocytes from these patients were cytotoxic to both types of cell lines, as were lymphocytes from healthy individuals. If, however, lymphocytes bearing complement receptors were removed, the residual IM lymphocyte fraction was specifically cytotoxic for EBV-genome-carrying cell lines. The residual lymphocyte fraction in normal donors had no such effect. Heterophile-positive IM is caused by EBV, and these results indicate that, during the acute phase of this disease, patients harbor killer cells, probably T cells, which specifically kill EBV-genome-carrying B cells in vitro. No such specificity for EBV-genome-positive target cells was found in normal lymphocytes stimulated in vitro with autologous EBV-genome-positive lymphoblastoid cells. Such stimulated cells were highly cytotoxic to both genome-positive and negative lines after removal of complement receptor-positive lymphocytes.The Epstein-Barr virus (EBV) has been regularly associated with three human diseases; infectious mononucleosis (IM) (1), Burkitt's lymphoma (BL) (2), and nasopharyngeal carcinoma (2). The etiologic role of this virus is clearly established in IM, whereas, it remains suggestive but not proven in BL and nasopharyngeal carcinoma. IM is characterized by an intensive lymphoproliferation which, although it sometimes resembles the acute phase of leukemia, always is self-limiting and benign in character. This self-limitation in viw is in contrast to the capacity of the patient's lymphocytes to proliferate indefinitely in vitro as continuous cell lines with surface characteristics typical for bone-marrow derived (B) lymphocytes (2). Such cell lines carry the EBV genome, as shown by nucleic acid hybridization or the presence of the EBV-associated nuclear antigen (EBNA) (2, 3). It would be essential to understand what mechanisms protect the IM patients from continuous lymphoproliferation.Recent investigations have shown that a high proportion of the blast-transformed cells found in the peripheral blood of IM patients are thymus-derived (T) lymphocytes (4-7).As T lymphocytes are known to be the major defense mechanism in many viral infections (8), we have studied the capacity of lymphocytes isolated from IM patients to kill a variety of cell lines that do or do not carry the EBV genome. Furthermore, we have compared the target cell specificity of the IM lymphocytes with the specificity of lymphocytes stimulated in vitro with autologous EBV-genome-carrying cell lines.

HLA antigen-related restriction of T lymphocyte cytotoxicity to Epstein-Barr virus.

“…Interestingly, our findings contrast with those of others who, using cytotoxic T cells from patients with acute infectious mononucleosis (IM), found no HLA-associated killing-of EBV-infected target cells (14,15) or HLA-associated killing but no allogeneic restriction (16). It should be emphasized, however, that although EB virus-specific memory T cells have been readily demonstrated in normal seropositive donors, they have not been detected in IM patients until at least 5-23 weeks after onset (17).…”

Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells

“…Several reports have shown that during IM the percentage of peripheral blood CD8 + lymphocytes increases while the percentage of CD4 + lymphocytes decreases (Reinherz et al, 1980;De Waele et al, 1981). Both CD4 ÷ and CD8 + subsets are activated, as determined by the upregulation of surface CD45RO (Miyawaki et al, 1991), and EBV-specific cytotoxic T lymphocytes (CTLs) can be detected (Svedmyr & Jondal, 1975;Royston et al, 1975). IM is usually self-limiting, and the relative levels of CD4 + and CD8 + T cells return to normal during convalescence (Reinherz et al, 1980).…”

In vitro immune responses to PPD, extracts from Raji cells and nasopharyngeal carcinoma biopsies in NPC leucocytes

“…Nkrumah et al (1976) reported that patients with Burkitt's lymphoma showed a positive skin reaction against a membrane extract of Raji cell, aind that the antigenic specificities of such reactivity did not appear to be directed against EBNA. Cytotoxic effector cells specific for Raji cells have also been found in the peripheral blood of patients with infectious mononucleosis during the acute phase of the disease (Svedmyr and Jondal, 1975). It seems possible from these studies and from others with animal tumour viruses (Habel, 1969) that there may exist a new class of plasmamembrane-associated EBV antigens which has not yet been defined serologically.…”