Antibodies to adhesion molecules inhibit the lytic function of MHC-unrestricted cytotoxic cells by preventing their activation.
We evaluated the effect of the antibodies to adhesion molecules CD2, CD11a/CD18 (LFA-1), and CD56 (N-CAM) on MHC-unrestricted cytotoxicity mediated by polyclonal NK cells and LAK cells or by CD3+ or CD3- cytolytic cell clones against a panel of tumor cell targets selected according to expression or absence of the corresponding ligands. We show that (i) antibodies to CD11a/CD18 and, to a lesser extent, antibodies to CD2 inhibit target cell lysis, whereas anti-CD56 antibodies exert little if any effect; (ii) in a model system using polyclonal NK/LAK cells as effectors and K562 or HL60-R (NK-resistant) cells as targets, inhibition of cytotoxicity occurs without a significant impairment of effector to target cell binding; (iii) the cytotoxic function of CD3+ or CD3- cytotoxic cell clones is inhibited differentially by antibodies to adhesion molecules; (iv) conjugates formed in the presence of antibodies which inhibit target cell lysis display a significant reduction of target to effector cell contact surface; and (v) this may lead to defective activation of effector cells, as indicated by lack of redistribution of the microtubular apparatus. We conclude that (i) MHC-unrestricted cytotoxicity is regulated by a number of molecular interactions that span far beyond our present knowledge and that it is strictly dependent on the surface phenotype of the effector cell and of the target cell; (ii) in certain types of effector/target cell interactions, antibodies to adhesion molecules do not prevent conjugate formation but reduce the extent of cell-to-cell surface contact which, in turn, leads to defective activation of the effector cell and, therefore, to inhibition of target cell lysis.
Zarcone
D
D
Istituto di Anatomia e Istologia, Università di Genova, Italy.
Viale
O
O
Cerruti
G
G
Tenca
C
C
Malorni
W
W
Arancia
G
G
Iosi
F
F
Galandrini
R
R
Velardi
A
A
Moretta
A
A
D000199:Actins / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000276:immunology; D018821:CD18 Antigens; D018801:CD2 Antigens; D017252:CD3 Complex; D019002:CD56 Antigen; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002478:Cells, Cultured; D002999:Clone Cells; D003599:Cytoskeleton / Q000648:ultrastructure; D003602:Cytotoxicity, Immunologic; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008855:Microscopy, Electron, Scanning; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D011971:Receptors, Immunologic / Q000276:immunology; D014404:Tubulin / Q000378:metabolism
D000199:Actins; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018821:CD18 Antigens; D018801:CD2 Antigens; D017252:CD3 Complex; D019002:CD56 Antigen; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D014404:Tubulin