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J. Biol. Chem., Vol. 276, Issue 30, 28068-28074, July 27, 2001
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From the Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
Engagement of antigen receptors on the surface of
T-cells with peptides bound to major histocompatibility complex (MHC)
proteins triggers T-cell activation in a mechanism involving receptor
oligomerization. Receptor dimerization by soluble MHC oligomers is
sufficient to induce several characteristic activation processes in
T-cells including internalization of engaged receptors and
up-regulation of cell surface proteins. In this work, the influence of
intermolecular orientation within the activating receptor dimer was
studied. Dimers of class II MHC proteins coupled in a variety of
orientations and topologies each were able to activate
CD4+ T-cells, indicating that triggering was not
dependent on a particular receptor orientation. In contrast to the
minimal influence of receptor orientation, T-cell triggering was
affected by the inter-molecular distance between MHC molecules, and MHC
dimers coupled through shorter cross-linkers were consistently more
potent than those coupled through longer cross-linkers. These results
are consistent with a mechanism in which intermolecular receptor
proximity, but not intermolecular orientation, is the key determinant
for antigen-induced CD4+ T-cell activation.
Receptor Proximity, Not Intermolecular Orientation, Is Critical
for Triggering T-cell Activation*
, and
*
This work was supported by National Institutes of Health
Grants N01AI95361 (to L. J. S.) and T32 GM08334 (to J. R. C., T. O. C., and J. D. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Current address: Dept. of Molecular Biophysics and Biochemistry,
Yale University, New Haven, CT 06527.
§
To whom correspondence should be addressed: Dept. of Chemistry,
Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139. Tel.: 617-253-2849; Fax: 617-258-7847; E-mail: stern@mit.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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