期刊
JOURNAL OF IMMUNOLOGY
卷 180, 期 12, 页码 8211-8221出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.180.12.8211
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资金
- NHLBI NIH HHS [T32 HL007195-30, T32 HL007195, T32 HL 07195-30] Funding Source: Medline
- NIAID NIH HHS [R01 AI074074, R01 AI 074074, R01 AI074074-18, R01 AI074074-17A1] Funding Source: Medline
The CD8 coreceptor contributes to the recognition of peptide-MHC (pMHC) ligands by stabilizing the TCR-pMHC interaction and enabling efficient signaling initiation. It is unclear though, which structural elements of the TCR ensure a productive association of the coreceptor. The alpha-chain connecting peptide motif (alpha-CPM) is a highly conserved sequence of eight amino acids in the membrane proximal region of the TCR alpha-chain. TCRs lacking the alpha-CPM respond poorly to low-affinity pMHC ligands and are unable to induce positive thymic selection. In this study we show that CD8 participation in ligand binding is compromised in T lineage cells expressing mutant alpha-CPM TCRs, leading to a slight reduction in apparent affinity; however, this by itself does not explain the thymic selection defect. By fluorescence resonance energy transfer microscopy, we found that TCR-CD8 association was compromised for TCRs lacking the alpha-CPM. Although high-affinity (negative-selecting) pMHC ligands showed reduced TCRCD8 interaction, low-affinity (positive-selecting) ligands completely failed to induce molecular approximation of the TCR and its coreceptor. Therefore, the alpha-CPM of a TCR is an important element in mediating CD8 approximation and signal initiation.
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