Interaction between the CD8 coreceptor and major histocompatibility complex class I stabilizes T cell receptor-antigen complexes at the cell surface

被引:135
作者
Wooldridge, L
van den Berg, HA
Glick, M
Gostick, E
Laugel, B
Hutchinson, SL
Milicic, A
Brenchley, JM
Douek, DC
Price, DA
Sewell, AK
机构
[1] Univ Oxford, Nuffield Dept Med, T Cell Modulat Grp, Oxford OX1 3SY, England
[2] Univ Kent, Inst Math Stat & Actuarial Sci, Canterbury CT2 7NF, Kent, England
[3] Novartis Inst Biomed Res, Cambridge, MA 02139 USA
[4] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA
基金
英国医学研究理事会; 英国惠康基金;
关键词
D O I
10.1074/jbc.M500555200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The off-rate (k(off)) of the T cell receptor (TCR)/peptide-major histocompatibility complex class I (pMHCI) interaction, and hence its half-life, is the principal kinetic feature that determines the biological outcome of TCR ligation. However, it is unclear whether the CD8 coreceptor, which binds pMHCI at a distinct site, influences this parameter. Although biophysical studies with soluble proteins show that TCR and CD8 do not bind cooperatively to pMHCI, accumulating evidence suggests that TCR associates with CD8 on the T cell surface. Here, we titrated and quantified the contribution of CD8 to TCR/pMHCI dissociation in membrane-constrained interactions using a panel of engineered pMHCI mutants that retain faithful TCR interactions but exhibit a spectrum of affinities for CD8 of > 1,000-fold. Data modeling generates a "stabilization factor" that preferentially increases the predicted TCR triggering rate for low affinity pMHCI ligands, thereby suggesting an important role for CD8 in the phenomenon of T cell cross-reactivity.
引用
收藏
页码:27491 / 27501
页数:11
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