Chiang Eugene Y, Stroynowski Iwona
Center for Immunology, Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
J Immunol. 2006 Aug 15;177(4):2123-30. doi: 10.4049/jimmunol.177.4.2123.
The mouse multimember family of Qa-2 oligomorphic class I MHC genes is continuously undergoing duplications and deletions that alter the number of the two "prototype" Qa-2 sequences, Q8 and Q9. The frequent recombination events within the Q region lead to strain-specific modulation of the cumulative Qa-2 expression levels. Q9 protects C57BL/6 hosts from multiple disparate tumors and functions as a major CTL restriction element for shared tumor-associated Ags. We have now analyzed functional and structural properties of Q8, a class I MHC that differs significantly from Q9 in the peptide-binding, CTL-interacting alpha(1) and alpha(2) regions. Unexpectedly, we find that the extracellular domains of Q8 and Q9 act similarly during primary and secondary rejection of tumors, are recognized by cross-reactive antitumor CTL, have overlapping peptide-binding motifs, and are both assembled via the transporter associated with the Ag processing pathway. These findings suggest that shared Ag-presenting functions of the "odd" and "even" Qa-2 loci may contribute to the selective pressures shaping the haplotype-dependent quantitative variation of Qa-2 protein expression.
小鼠Qa-2寡态性I类MHC基因的多成员家族不断经历重复和缺失，从而改变了两个“原型”Qa-2序列Q8和Q9的数量。Q区域内频繁的重组事件导致Qa-2累积表达水平的品系特异性调节。Q9保护C57BL/6宿主免受多种不同肿瘤的侵害，并作为共享肿瘤相关抗原的主要CTL限制元件发挥作用。我们现在分析了Q8的功能和结构特性，Q8是一种I类MHC，在肽结合、与CTL相互作用的α(1)和α(2)区域与Q9有显著差异。出乎意料的是，我们发现Q8和Q9的细胞外结构域在肿瘤的初次和二次排斥反应中表现相似，被交叉反应性抗肿瘤CTL识别，具有重叠的肽结合基序，并且都通过与抗原加工途径相关的转运体组装。这些发现表明，“奇数”和“偶数”Qa-2位点共享的抗原呈递功能可能有助于形成塑造Qa-2蛋白表达单倍型依赖性定量变异的选择压力。
