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Receptor proximity, not intermolecular orientation, is critical for triggering T-cell activation
J R Cochran1, T O Cameron, J D Stone
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
The Journal of Biological Chemistry
|June 1, 2001
Summary
T-cell activation depends on proximity, not orientation, of major histocompatibility complex (MHC) dimers. Shorter distances between MHC molecules enhance T-cell triggering, revealing key factors in antigen-induced immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Signaling
Background:
- T-cell activation is initiated by antigen receptors engaging peptide-MHC complexes.
- Receptor oligomerization, particularly dimerization, is a known trigger for T-cell activation.
- Previous studies show soluble MHC oligomers can induce T-cell activation markers.
Purpose of the Study:
- To investigate the role of intermolecular orientation within activating receptor dimers.
- To determine the impact of distance between major histocompatibility complex (MHC) molecules on T-cell activation.
- To elucidate the key structural determinants for antigen-induced CD4+ T-cell activation.
Main Methods:
- Construction of class II MHC dimers with varied intermolecular orientations and topologies.
- Assessment of T-cell activation in response to different MHC dimer configurations.
- Analysis of receptor internalization and cell surface protein up-regulation as activation markers.
Main Results:
- All tested MHC dimer orientations and topologies successfully activated CD4+ T-cells.
- T-cell activation was independent of the specific intermolecular orientation of the MHC dimer.
- MHC dimers with shorter cross-linkers (smaller intermolecular distance) were more potent activators than those with longer cross-linkers.
Conclusions:
- Intermolecular proximity between MHC molecules is critical for T-cell activation.
- Intermolecular orientation within the MHC dimer does not significantly influence T-cell triggering.
- These findings support a model where close spacing of MHC molecules is the primary determinant for antigen-induced T-cell activation.