Downregulation of cell adhesion molecules LFA-3 and ICAM-1 in Epstein-Barr virus-positive Burkitt's lymphoma underlies tumor cell escape from virus-specific T cell surveillance.

Abstract

Cell surface adhesion molecules are thought to play an important part in establishing the intercellular contacts that are necessary for immunological reactions (1). One such adhesion pathway in man involves the lymphocyte function-associated antigen (LFA-1), ' one of a family of leukocyte cell surface proteins (LFA-1, Mac-1, p150, 95) that are heterodimers with a common (3 chain and distinct though homologous a chains (1, 2). The principal ligand for LFA-1 seems to be the intercellular adhesion molecule ICAM-1, a protein expressed on many differentiated cell types (3) . The LFA-1/ICAM-1 pathway mediates a variety of cell-cell adhesions by T and B lymphocytes, natural killer cells, granulocytes, and macrophages (1-5) and also appears to be responsible for the homotypic cell adhesions shown by certain leukocytederived cell lines in vitro (5).Interactions between cytotoxic T lymphocytes (CTL) and their target cells involve an initial phase of effector/target adhesion, detectable by rapid conjugate formation in vitro, which is independent ofantigen-specific recognition (4). mAb blocking studies indicate that this interaction involves two separate adhesion pathways (4, fi). One is the effector LFA-1/target ICAM-1 pathway described above, the other is mediated via the T cell-specific CD2 antigen (T11, LFA-2) interacting with a widely distributed adhesion protein, LFA-3 (7), on the target cell surface. Both pathways appear to be required for optimal effector/target conjugation, and therefore might be important accessories for CTL formation.One of the best characterized CTL surveillance systems operative in man is that which is specifically directed against Epstein-Barr virus (EBV), an agent with oncogenic potential in vivo (8) and with cell growth transforming ability for human B cells in vitro (9). EBVspecific CTL, reactivated from memory T cells in the blood of virus-immune donors, recognize EBVtransformed B lymphoblastoid cell lines (LCL) in a HLA class I antigen-restricted manner (10) .

Regulation of LFA‐1‐mediated T cell adhesion by CD4

“…LFA-1 (CDlla-CD18) binding to ICAM-1 (CD54) or ICAM-2 ligands and CD2 binding to LFA-3 (LCD58; [1][2][3]), Such adhesion processes are required for T cell activation and effector functions. This has been demonstrated in blocking experiments using specific mAb [4][5][6] and showing altered binding and functions of T ceils defective in LFA-1 expres sion [6][7][8], as well as poor binding and cytotoxic function of T cells towards ICAM-1" LFA-3" Burkitt B cells [9]. Finally, transfection of murine fibroblasts with ICAM-1 or LFA-3, in association with MHC molecules, leads to optimal binding and activation of specific T cells [10][11][12].…”

Different Epstein--Barr virus--B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line

“…Thus, whilst target cells at a number of different stages of B cell differentiation can be transformed by EBV in vitro, the cell lines so produced all display the same 'lymphoblastoid' phenotype as defined by cell surface marker analysis and growth in cell aggregates (Katamine et al, 1984;Ernberg et al, 1987;Gregory et al, 1987aGregory et al, , 1988a. In particular, such in vitro transformed lines reproducibly express high levels of the B cell activation antigens CD23, CD30, CD39 and CD70 Rowe et aL, 1985), and 0000-9420 © 1990 SGM of the cellular adhesion molecules LFA-1 (CD1 la/18), ICAM-1 (CD54), LFA-3 (CD58) (Gregory et al, 1988b) and the lymphocyte homing receptor CD44 (C. D. Gregory, unpublished observations). It is significant that these same markers, which are either absent or found at very low levels on resting B cells, are also induced transiently to high levels when such cells are activated into short-term proliferation by antigenic or mitogenic stimulation Gordon, 1989).…”

“…Indirect immunofluorescence staining of viable cells was carried out using MAbs as described (Gregory et al, 1988b). Surface immunofluorescence was either assessed by microscopy or measured on a fluorescence-activated cell sorter (FACS 440,.…”

Presentation of CMV immediate-early antigen to cytolytic T lymphocytes is selectively prevented by viral genes expressed in the early phase

“…owing to very low surface levels of accessory adhesion molecules, constitute poor targets tor antiviral CTLs (Gregory et al, 1988). As expected, and as actually shown 10r class I molecules (Yewdeli et al, 1988), the reduction in the surface levels of cell membrane proteins required 10r antigen presentation and target cell recognition by CTLs indiscriminately prevents effieient reeognition of any antigen.…”

“…Because of its selectivity, the inhibition of pp89 presentation is unlike other reported cases of interference with antigen recognition by CTLs, all of which could be explained by a general decrease in the surface levels of ce 1-lular presenting or adhesion moleeules (Gooding, 1982;Bernards et al , 1983;Jennings et al, 1985;Masucci et al , 1987;Gregory et al. 1988) that indiscriminately affects the presentation of any antigen.…”