title: Coengagement of CD2 with LFA-1 or VLA-4 by bispecific ligand fusion proteins primes T cells to respond more effectively to T cell receptor-dependent signals.
abstract: To examine the effects of ligand engagement and accessory molecule juxtaposition on T cell receptor (TCR) signaling, we prepared LFA-3/ICAM-1 Rg and LFA-3/VCAM-1 Rg bispecific immunoglobulin fusion proteins (Rg, recombinant globulin). These novel fusion proteins allowed us to examine the effects of ligand driven co-engagement of T cell proteins CD2 and LFA-1 or CD2 and VLA-4 on TCR-dependent mobilization of intracellular Ca2+. We observed that preincubation of resting T cells with LFA-3/ICAM-1 Rg or LFA-3/VCAM-1 Rg fusion proteins resulted in significantly enhanced mobilization of intracellular Ca2+ following TCR-accessory molecule cross-linking relative to T cells preincubated with each of the monospecific Rgs alone or with combinations of the monospecific Rg fusion proteins. In addition, such coengagement stimulated TCR-dependent activation and tyrosine phosphorylation of phospholipase C gamma 1 (PLC gamma 1). These results suggest that when T cells interact with antigen presenting cells the engagement of multiple cell adhesion molecules such as CD2, LFA-1, and VLA-4 primes the T cell to respond more effectively to signals delivered through the TCR.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
authors.forename: M T
authors.initials: MT
authors.lastname: Dietsch
authors.forename: P Y
authors.initials: PY
authors.lastname: Chan
authors.forename: S B
authors.initials: SB
authors.lastname: Kanner
authors.forename: L K
authors.initials: LK
authors.lastname: Gilliland
authors.forename: J A
authors.initials: JA
authors.lastname: Ledbetter
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
mesh_terms: D018033:Antibodies, Bispecific; D015703:Antigens, CD / Q000502:physiology; D018801:CD2 Antigens / Q000502:physiology*; D017252:CD3 Complex / Q000502:physiology; D018968:CD58 Antigens; D002118:Calcium / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D011940:Receptor Aggregation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D016029:Receptors, Very Late Antigen / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D018033:Antibodies, Bispecific; D015703:Antigens, CD; D018801:CD2 Antigens; D017252:CD3 Complex; D018968:CD58 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D016029:Receptors, Very Late Antigen; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1; D002118:Calcium