title: Heterodimeric complex formation with CD8 and TCR by bispecific antibody sustains paracrine IL-2-dependent growth of CD3+ CD8+ T cells.
abstract: During physiologic activation of mature CD8+ T cells, TCR and CD8 bind to the same Ag-complexed MHC class I molecule. Thereby, close proximity is induced between CD8 and the TCR/CD3 complex. During this engagement, CD8 may deliver TCR-independent signals via its associated protein tyrosine kinase, p56lck. We studied the potential biologic effects of close association between CD8 and TCR/CD3 complexes by using a bispecific antibody (bsAb) directed against both TCR and CD8 molecules. This hybrid hybridoma (quadroma)-produced bsAb binds as a monomeric molecule to CD3+ CD8+ but not CD3+ CD4+ T cells. The bsAb proved capable of inducing the cytotoxic effector function of cloned CD3+ CD8+ T cells but not of CD3+ CD4+ T cells. When the bsAb was presented to resting T cells by monocytes, proliferation of the CD3+ CD4+ but not the CD3+ CD8+ subset of T lymphocytes was induced. Parental anti-TCR antibody induced vigorous growth of cells of both subsets. Essentially identical results were obtained when bsAb was presented in an immobilized fashion. The unresponsiveness of the CD3+ CD8+ T cells with respect to mitogenesis could be restored by exogenous rIL-2. The data suggest that bsAb-induced activation differs from activation by monospecific anti-TCR antibody. The former appears to more closely mimic physiologic Ag-induced signaling, because it leads to a similar paracrine IL-2-dependent growth pattern. The bsAb may, therefore, be instrumental in studying T cell signaling pathways, in particular the role of CD8-associated p56lck therein.
authors.affiliation: Department of Clinical Immunology, University Hospital, Utrecht, The Netherlands.
authors.forename: W B
authors.initials: WB
authors.lastname: De Lau
authors.forename: S E
authors.initials: SE
authors.lastname: Boom
authors.forename: K
authors.initials: K
authors.lastname: Heije
authors.forename: A W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: E
authors.initials: E
authors.lastname: Braakman
authors.forename: R L
authors.initials: RL
authors.lastname: Bolhuis
authors.forename: W J
authors.initials: WJ
authors.lastname: Tax
authors.forename: H
authors.initials: H
authors.lastname: Clevers
authors.forename: B J
authors.initials: BJ
authors.lastname: Bast
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D017252:CD3 Complex; D016827:CD8 Antigens / Q000737:chemistry / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007158:Immunologic Techniques; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000502:physiology*; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D011940:Receptor Aggregation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D012995:Solubility; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D016827:CD8 Antigens; D007376:Interleukin-2; D046911:Macromolecular Substances; D011948:Receptors, Antigen, T-Cell; D002118:Calcium