Role of the adhesion molecule ICAM-1 (CD54) in staphylococcal enterotoxin-mediated cytotoxicity.
Staphylococcal enterotoxin A (SEA) binds to major histocompatibility complex (MHC) class II molecules on target cells and directs human cytotoxic T lymphocytes (CTL) of irrelevant nominal specificity to mediate strong cytotoxicity against target cells. In this report we describe the importance of ICAM-1 (CD54) expression on the target cell in SEA-dependent cell-mediated cytotoxicity (SDCC), utilizing murine L cells co-transfected with HLA-DR and ICAM-1. Human CTL mediated a low but significant cytotoxicity against HLA-DR2- and HLA-DR7-transfected cells after preincubation with SEA, but no reactivity towards uncoated HLA-DR2 and HLA-DR7 cells or SEA-coated ICAM-1-transfected and untransfected L cells. In contrast, a strong cytotoxic response was mediated by CTL against L cells co-transfected with HLA-DR2/ICAM-1 and HLA-DR7/ICAM-1. Similar cytotoxic activity of the CTL was seen at a 30-fold lower effector-to-target cell ratio when comparing the HLA-DR2/ICAM-1-expressing cells with the HLA-DR2-expressing cells. SEA dose-response analysis demonstrated that the HLA-DR2/ICAM-1-expressing target cells enabled the CTL to respond to a 1000-fold lower concentration of SEA in comparison to the HLA-DR2-expressing cells. CD3+CD4+ and CD3+CD8+ cytotoxic T cell lines were equally dependent on the expression of ICAM-1 on the target cell. The strong CTL activity against HLA-DR2/ICAM-1-transfected cells could be blocked by anti-CD11a or anti-CD18 monoclonal antibodies (mAb), but not by anti-CD11b, anti-CD11c, anti-CD2 or unrelated control mAb. The great sensitivity of HLA-DR2/ICAM-1 expressing target cells to SDCC was strongly reduced by preincubation with various anti-ICAM-1 mAb but not by mAb against monomorphic HLA-DR or murine MHC class I determinants. The result in this study clearly demonstrates that efficient re-targeting of human CTL by SE is dependent on a proper interaction with the heterodimer CD11a/CD18 (Leu-CAMa, LFA-1) on the CTL and its target cell ligand ICAM-1.
Dohlsten
M
M
Pharmacia-LEO Therapeutics AB, Malmö, Sweden.
Hedlund
G
G
Lando
P A
PA
Trowsdale
J
J
Altmann
D
D
Patarroyo
M
M
Fischer
H
H
Kalland
T
T
D000911:Antibodies, Monoclonal; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000502:physiology*; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000633:toxicity*; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1; D007739:L Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis; D016028:Receptors, Leukocyte-Adhesion / Q000032:analysis; D013211:Staphylococcus aureus / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D004768:Enterotoxins; D006684:HLA-DR Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D016028:Receptors, Leukocyte-Adhesion; D018799:Intercellular Adhesion Molecule-1; C026066:enterotoxin A, Staphylococcal