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Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152).


J Immunol. 2000 May 1;164(9):4433-42. Unique Identifier : AIDSLINE

CTLA-4 (CD152) engagement can down-regulate T cell activation and promote the induction of immune tolerance. However, the strategy of attenuating T cell activation by engaging CTLA-4 has been limited by sharing of its natural ligands with the costimulatory protein CD28. In the present study, a CTLA-4-specific single-chain Ab (scFv) was developed and expressed on the cell surface to promote selective engagement of this regulatory molecule. Transfectants expressing anti-CTLA-4 scFv at their surface bound soluble CTLA-4 but not soluble CD28. Coexpression of anti-CTLA-4 scFv with anti-CD3epsilon and anti-CD28 scFvs on artificial APCs reduced the proliferation and IL-2 production by resting and preactivated bulk T cells as well as CD4+ and CD8+ T cell subsets. Importantly, expression of anti-CTLA-4 scFv on the same cell surface as the TCR ligand was essential for the inhibitory effects of CTLA-4-specific ligation. CTLA-4-mediated inhibition of tyrosine phosphorylation of components of the proximal TCR signaling apparatus was similarly dependent on coexpression of TCR and CTLA-4 ligands on the same surface. These findings support a predominant role for CTLA-4 function in the modification of the proximal TCR signal. Using T cells from DO11.10 and 2C TCR transgenic mice, negative regulatory effects of selective CTLA-4 ligation were also demonstrated during the stimulation of Ag-specific CD4+ and CD8+ T cells by MHC/peptide complexes. Together these studies demonstrate that selective ligation of CTLA-4 using a membrane-bound scFv results in attenuated T cell responses only when coengaged with the TCR during T cell/APC interaction and define an approach to harnessing the immunomodulatory potential of CTLA-4-specific ligation.

JOURNAL ARTICLE Amino Acid Sequence Animal Antibodies, Blocking/BIOSYNTHESIS/GENETICS/METABOLISM/ *PHARMACOLOGY Antibody Specificity/GENETICS Antigens, Differentiation/*IMMUNOLOGY/METABOLISM Cell Line Cytokines/BIOSYNTHESIS/SECRETION CD4-Positive T-Lymphocytes/IMMUNOLOGY CD8-Positive T-Lymphocytes/IMMUNOLOGY Female Human Immunoglobulin Variable Region/BIOSYNTHESIS/*IMMUNOLOGY/ METABOLISM Immunoglobulins, Surface/BIOSYNTHESIS/GENETICS/*IMMUNOLOGY/ METABOLISM Interphase/GENETICS/IMMUNOLOGY Ligands Lymphocyte Transformation/GENETICS/*IMMUNOLOGY Major Histocompatibility Complex/GENETICS/IMMUNOLOGY Mice Mice, Inbred BALB C Mice, Transgenic Molecular Sequence Data Peptides/GENETICS/IMMUNOLOGY Receptors, Antigen, T-Cell/IMMUNOLOGY/METABOLISM Signal Transduction/GENETICS/IMMUNOLOGY Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. T-Lymphocyte Subsets/IMMUNOLOGY Transfection Tumor Cells, Cultured


Information in this article was accurate in July 30, 2000. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.