The role of lymphocyte subsets and adhesion molecules in T cell-dependent cytotoxicity mediated by CD3 and CD28 bispecific monoclonal antibodies.
The cure of human Hodgkin's tumors heterotransplanted into SCID mice can be achieved by two bispecific monoclonal antibodies (Bi-mAb) directed against the tumor-associated CD30 antigen and CD3 and CD28, respectively, and normal peripheral human blood T cells. We investigated the role of lymphocyte subsets and adhesion molecules in this Bi-mAb-mediated cytolysis. CD4+ lymphocytes were the most rapidly expanding subpopulation, but Bi-mAb-directed cytotoxicity was mediated preferentially by CD8+ lymphocytes and effector cells belonging to the CD45RO+ "memory" pool. Blocking of the LFA-1/ICAM-1 or CD2/LFA-3 adhesion pathways by mAb decreased Bi-mAb-mediated cytotoxicity. This was not due to inhibition of aggregate formation between Bi-mAb-coated T lymphocytes and target cells. Cross-linking of LFA-1 or CD2 molecules on lymphocytes prestimulated with Bi-mAb bound to CD3 and CD28 antigen lead to a more pronounced and prolonged rise in the intracellular concentration of free Ca2+. Additional CD2 cross-linking resulted in the tyrosine phosphorylation of distinct proteins. These findings indicate that adhesion molecules play a critical role and function as co-stimulatory signals rather than as cellular contact mediators in CD3 and CD28 Bi-mAb-stimulated T lymphocytes.
Renner
C
C
Medizinische Klinik I. Universität des Saarlandes, Homburg, Germany.
Jung
W
W
Sahin
U
U
van Lier
R
R
Pfreundschuh
M
M
D018033:Antibodies, Bispecific; D018106:CD28 Antigens / Q000502:physiology*; D017252:CD3 Complex / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D017730:Ki-1 Antigen / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000276:immunology*; D008285:Major Histocompatibility Complex; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018033:Antibodies, Bispecific; D018106:CD28 Antigens; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D017730:Ki-1 Antigen; D010750:Phosphoproteins; D002118:Calcium