Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice.
Soluble ligands specific for cell surface molecules involved in APC-T cell interactions can signal cells and modulate immune responses. Recently, we reported that LFA3TIP, a fusion protein comprised of the first LFA-3 extracellular domain fused to the hinge, CH2, and CH3 regions of a human IgG1 inhibits proliferation of human T cells in vitro. We report herein the cell-based mechanism(s) of LFA3TIP in inhibition by studying the effects of structurally altered LFA3-Ig fusion proteins on proliferation of human PBL in vitro and on responses of mice transgenic for human CD2. We show that LFA3TIP inhibition requires expression of both the LFA-3 and CH2 domains of the fusion protein that bind CD2 and Fc gamma RI or Fc gamma RIII, respectively. LFA3TIP forms an intracellular Fc gamma R/CD2 bridge and directs cytolysis of CD2+ cells by freshly drawn human PBL in vitro as well as the non-C-mediated depletion of peripheral T cells of human CD2 transgenic mice. The cell-based mechanism(s) of LFA3TIP inhibition are discussed.
Majeau
G R
GR
Biogen Inc., Cambridge, MA 02142.
Meier
W
W
Jimmo
B
B
Kioussis
D
D
Hochman
P S
PS
D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D018801:CD2 Antigens; D018968:CD58 Antigens; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017452:Receptors, IgG / Q000032:analysis; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D018968:CD58 Antigens; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins