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      Topological Requirements and Signaling Properties of T Cell–activating, Anti-CD28 Antibody Superagonists

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          Abstract

          Full activation of naive T cells requires both engagement of the T cell antigen receptor (TCR; signal 1) and costimulatory signaling by CD28 (signal 2). We previously identified two types of rat CD28-specific monoclonal antibodies (mAbs): “conventional,” TCR signaling–dependent costimulatory mAbs and “superagonistic” mAbs capable of inducing the full activation of primary resting T cells in the absence of TCR ligation both in vitro and in vivo. Using chimeric rat/mouse CD28 molecules, we show that the superagonists bind exclusively to the laterally exposed C′′D loop of the immunoglobulin-like domain of CD28 whereas conventional, costimulatory mAbs recognize an epitope close to the binding site for the natural CD80/CD86 ligands. Unexpectedly, the C′′D loop reactivity of a panel of new antibodies raised against human CD28 could be predicted solely on the basis of their superagonistic properties. Moreover, mouse CD28 molecules engineered to express the rat or human C′′D loop sequences activated T cell hybridomas without TCR ligation when cross-linked by superagonistic mAbs. Finally, biochemical analysis revealed that superagonistic CD28 signaling activates the nuclear factor κB pathway without inducing phosphorylation of either TCRζ or ZAP70. Our findings indicate that the topologically constrained interactions of anti-CD28 superagonists bypass the requirement for signal 1 in T cell activation. Antibodies with this property may prove useful for the development of T cell stimulatory drugs.

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          Most cited references 43

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            Improved methods for building protein models in electron density maps and the location of errors in these models.

            Map interpretation remains a critical step in solving the structure of a macromolecule. Errors introduced at this early stage may persist throughout crystallographic refinement and result in an incorrect structure. The normally quoted crystallographic residual is often a poor description for the quality of the model. Strategies and tools are described that help to alleviate this problem. These simplify the model-building process, quantify the goodness of fit of the model on a per-residue basis and locate possible errors in peptide and side-chain conformations.
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              A cell culture model for T lymphocyte clonal anergy.

              T lymphocytes respond to foreign antigens both by producing protein effector molecules known as lymphokines and by multiplying. Complete activation requires two signaling events, one through the antigen-specific receptor and one through the receptor for a costimulatory molecule. In the absence of the latter signal, the T cell makes only a partial response and, more importantly, enters an unresponsive state known as clonal anergy in which the T cell is incapable of producing its own growth hormone, interleukin-2, on restimulation. Our current understanding at the molecular level of this modulatory process and its relevance to T cell tolerance are reviewed.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                21 April 2003
                : 197
                : 8
                : 955-966
                Affiliations
                [1 ]Institute for Virology and Immunobiology, University of Würzburg, D-97078 Würzburg, Germany
                [2 ]TeGenero ImmunoTherapeutics AG, D-97076 Würzburg, Germany
                [3 ]Division of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
                [4 ]Nuffield Department of Medicine, The University of Oxford, Oxford OX3 9DU, United Kingdom
                Author notes

                Address correspondence to Thomas Hünig, Institute for Virology and Immunobiology, University of Würzburg, Versbacher Str. 7, D-97078 Würzburg, Germany. Phone: 49-931-20149951; Fax: 49-931-20149243; E-mail: huenig@ 123456vim.uni-wuerzburg.de

                Article
                20021024
                10.1084/jem.20021024
                2193880
                12707299
                Copyright © 2003, The Rockefeller University Press
                Categories
                Article

                Medicine

                cd28, costimulation, t cells, lymphocyte activation, receptor structure

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