A mechanistic study of immune system activation by fusion of antigens with the ligand-binding domain of CTLA4.
Fusion proteins consisting of the ligand-binding domain of CTLA4 covalently attached to an antigen (Ag) are potent immunogens. This fusion strategy effectively induces Ag-specific immunity both when introduced as a DNA-based vaccine and as a recombinant protein. CTLA4 is a ligand for B7 molecules expressed on the surface of antigen-presenting cells (APCs), and this interaction is critical for the fusion protein to stimulate Ag-specific immunity. We show that interaction of the fusion protein with either B7-1 or B7-2 is sufficient to stimulate immune activity, and that T cells are essential for the development of IgG responses. In addition, we demonstrate that human dendritic cells (DCs) pulsed with CTLA4-Ag fusion proteins can efficiently present Ag to T cells and induce an Ag-specific immune response in vitro. These studies provide further mechanistic understanding of the process by which CTLA4-Ag fusion proteins stimulate the immune system, and represent an efficient means of generating Ag-specific T cells for immunotherapy.
Chinnasamy
Dhanalakshmi
D
Immunotherapy Program, Aurora St. Luke's Medical Center, Aurora Health Care, Milwaukee, WI 53215, USA.
Tector
Matt
M
Chinnasamy
Nachimuthu
N
Dennert
Kate
K
Kozinski
Karen M
KM
Oaks
Martin K
MK
D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics*; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D060908:CTLA-4 Antigen; D003713:Dendritic Cells / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D007074:Immunoglobulin G; D008024:Ligands; D011993:Recombinant Fusion Proteins