The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published 21 April 2003. doi:10.1084/jem.20021024
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© Rockefeller University Press, 0022-1007/2003/4/955 $5.00
The Journal of Experimental Medicine, Volume 197, Number 8, 955-966

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

Fred Lühder1, Yun Huang1,2, Kevin M. Dennehy1, Christine Guntermann2, Ingrid Müller1, Erna Winkler2, Thomas Kerkau1, Shinji Ikemizu3, Simon J. Davis4, Thomas Hanke1,2 and Thomas Hünig1

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

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{at}vim.uni-wuerzburg.de

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 {kappa}B pathway without inducing phosphorylation of either TCR{zeta} 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.

Key Words: costimulation • CD28 • T cells • lymphocyte activation • receptor structure


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