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On page 579, Sumen et al. show that some mutant variants of antigens disable T cells by preventing the clustering of MHC molecules at the interface between T cells and antigen-presenting cells (APCs). The results also suggest that integrins are not the entire answer to getting T cells to stop at their targets.
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Certain antigen variants, called antagonists, interfere with a T cell's ability to respond to otherwise stimulatory antigens. Although they are often effective only at high concentrations, antagonists may be used—either by pathogens or as therapies against autoimmune diseases—to thwart strong defense responses. But just how they get in the way is unclear. In the new work, the authors show ways in which antagonists hinder the formation of the immunological synapse—the junction between the T cell and the APC that contains peptide-MHC molecules, T cell receptors (TCRs), and adhesion proteins.# i$ j$ f# A! T9 y M; U
1 L" v9 h: E! v- K' HSynapses that formed on membranes containing excess antagonists were sparse in MHC clusters. Fewer MHCs means less T cell proliferation and cytokine production, probably because fewer TCRs are engaged. Even long after antagonist was removed, the T cells still did not respond when exposed to active antigens. In their half-active state, T cells migrated past their antigenic targets rather than making the normal full stop.6 m* f6 U5 P2 F7 p5 C8 W6 K8 q7 @
" n; L7 J m. ]) ?( |: C& i+ V; cThis crippling of T cell adhesion appears to result from a failure to focus adhesion rather than a failure in integrin activation itself. The ICAM-1 adhesion molecule, which is a measure of active integrins, was equally dense in synapses with or without antagonists. With antagonists, ICAM-1 accumulated in a crescent shape, not the tight circular pattern characteristic of a strong synapse. ICAM-1 is probably pushed into this odd pattern by the continued cell movement.(ICAM-1 forms a sickle-like shape on T ce) |
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发表于 2009-3-6 08:17
发表于 2015-6-5 11:59
