title: Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses.
abstract: Accessory cell surface molecules, such as T cell antigen CD2 and its ligand lymphocyte function-associated antigen 3 (LFA-3; CD58), are critical costimulatory pathways for optimal T cell activation in response to antigens. Interaction of CD2 with cell surface LFA-3 not only increases T cell/accessory cell adhesion, but also induces signal transduction events involved in the regulation of T cell responses. In this report, we show that specific interactions of LFA-3 with CD2 can result in T cell unresponsiveness to antigenic or mitogenic stimuli in vitro. By deletion of certain regions of the extracellular domain of LFA-3, we localized the CD2 binding site to the first domain of LFA-3. We then demonstrated that a soluble, purified first domain-LFA-3/IgG1 fusion protein (LFA3TIP) interacts with CD2 and binds to the same CD2 epitope as purified multimeric or cell surface-expressed LFA-3. LFA3TIP inhibits tetanus toxoid, hepatitis B surface antigen, anti-CD3 mAb, Con A, and phytohemagglutinin P-induced T cell proliferation, as well as xenogeneic and allogeneic mixed lymphocyte reactions (MLR). Unlike anti-LFA-3 or anti-CD2 monoclonal antibodies (mAbs) which inhibit T cell responses by blocking LFA-3/CD2 binding, LFA3TIP is capable of rendering T cells unresponsive to antigenic stimuli in situations where T cell activation is independent of CD2/LFA-3 interactions. Furthermore, LFA3TIP, but not blocking anti-CD2 mAbs, is capable of inducing T cell unresponsiveness to secondary stimulation in allogeneic MLR. This inhibition of T cell responses by LFA3TIP occurs through a different mechanism from that of mAbs to LFA-3 or CD2.
authors.affiliation: Biogen, Inc, Cambridge, Massachusetts 02142.
authors.forename: G T
authors.initials: GT
authors.lastname: Miller
authors.forename: P S
authors.initials: PS
authors.lastname: Hochman
authors.forename: W
authors.initials: W
authors.lastname: Meier
authors.forename: R
authors.initials: R
authors.lastname: Tizard
authors.forename: S A
authors.initials: SA
authors.lastname: Bixler
authors.forename: M D
authors.initials: MD
authors.lastname: Rosa
authors.forename: B P
authors.initials: BP
authors.lastname: Wallner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D018801:CD2 Antigens; D018968:CD58 Antigens; D016466:CHO Cells; D006224:Cricetinae; D000939:Epitopes; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D011961:Receptors, Fc / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D018968:CD58 Antigens; D000939:Epitopes; D008562:Membrane Glycoproteins; D011961:Receptors, Fc; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins