CTLA-4 (CD152) Can Inhibit T Cell Activation by Two Different Mechanisms Depending on Its Level of Cell Surface Expression

• Published in: The Journal of immunology (1950) 2000-08, Vol.165 (3), p.1352-1356
• Main Authors: Carreno, Beatriz M, Bennett, Frann, Chau, Thu A, Ling, Vincent, Luxenberg, Deborah, Jussif, Jason, Baroja, Miren Lorea, Madrenas, Joaquin
• Format: Article
• Language: English
• Subjects: AB7 antigen; Abatacept; Amino Acid Sequence; Antibodies, Monoclonal - pharmacology; Antigens, CD - immunology; Antigens, Differentiation - biosynthesis; Antigens, Differentiation - genetics; Antigens, Differentiation - immunology; Antigens, Differentiation - physiology; B7-1 Antigen - physiology; B7-2 Antigen; CD152 antigen; CD28 Antigens - immunology; CD3 Complex - immunology; Cell Membrane - immunology; Cell Membrane - metabolism; CTLA-4 Antigen; CTLA-4 protein; Cytoplasm - immunology; Down-Regulation - immunology; Doxycycline - pharmacology; Humans; Immunoconjugates; Immunoglobulin Fc Fragments - genetics; Immunoglobulin Fc Fragments - physiology; Immunosuppressive Agents - pharmacology; Interleukin-2 - biosynthesis; Jurkat Cells; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Membrane Glycoproteins - immunology; Microspheres; Molecular Sequence Data; Peptide Fragments - immunology; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - pharmacology; Signal Transduction - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.3.1352

CTLA-4 (CD152) engagement results in down-regulation of T cell activation. Two mechanisms have been postulated to explain CTLA-4 inhibition of T cell activation: negative signaling and competitive antagonism of CD28:B7-mediated costimulation. We assessed the contributions of these two mechanisms using a panel of T cell lines expressing human CTLA-4 with mutations in the cytoplasmic region. Under conditions of B7-independent costimulation, inhibition of IL-2 production following CTLA-4 engagement required the CTLA-4 cytoplasmic region. In contrast, under B7-dependent costimulation, inhibition of IL-2 production by CTLA-4 engagement was directly proportional to CTLA-4 cell surface levels and did not require its cytoplasmic region. Thus, CTLA-4 down-regulates T cell activation by two different mechanisms-delivery of a negative signal or B7 sequestration-that are operational depending on the levels of CTLA-4 surface expression. These two mechanisms may have distinct functional outcomes: rapid inhibition of T cell activation or induction of T cell anergy.