当前位置: 首页 > 期刊 > 《实验药学杂志》 > 2005年第8期 > 正文
编号:11341711
Perfecting peptide priming
http://www.100md.com 《实验药学杂志》
     Slight alterations in peptide sequence alter the peptide–HLA–TCR interaction and affect T cell priming.

    A single amino acid change in a tumor-derived peptide results in the priming of a bigger and better T cell response upon vaccination, according to a study by Chen et al. on page 1243. Thus, results obtained with the original peptide, which is in phase I clinical trials as an anticancer vaccine, may be further enhanced by using the modified peptide.

    Single amino acid changes in peptides can either enhance or inhibit activation of the T cells whose T cell receptors (TCRs) bind the peptide–HLA complex. Structural alterations in the HLA–peptide–TCR complex are thought to cause these functional changes, although how structural changes modify the signaling events inside the T cell is not completely understood.

    To address this question, Chen et al. crystallized peptide–HLA–TCR complexes using either a wild-type tumor peptide or a variant peptide containing a cysteine to valine mutation at the COOH-terminal residue—a mutation they had previously shown to enhance killing of peptide-coated target cells by cytotoxic T cells. The altered peptide bound to the HLA molecule more tightly and created a longer lasting, more snug fit between the peptide–HLA complex and the TCR.

    This cozier interaction caused T cells to polarize their lytic granules toward target cells more rapidly and produce more cytokines upon target cell contact. The authors think that the tailored complex optimizes signaling events at the immunological synapse. Indeed, T cells stimulated with the altered peptide were less dependent on the CD8 coreceptor, which is necessary to stabilize some lower affinity TCR–HLA interactions.Immunization of mice with the tighter fitting peptide primed more interferon-–producing T cells than were primed by the wild-type peptide, suggesting that vaccines that use the altered peptide vaccine may produce a superior T cell response.(Heather L. Van Epps)