Assarsson Erika, Sidney John, Oseroff Carla, Pasquetto Valerie, Bui Huynh-Hoa, Frahm Nicole, Brander Christian, Peters Bjoern, Grey Howard, Sette Alessandro
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
J Immunol. 2007 Jun 15;178(12):7890-901. doi: 10.4049/jimmunol.178.12.7890.
Many components contribute to immunodominance in the response to a complex virus, but their relative importance is unclear. This was addressed using vaccinia virus and HLA-A0201 as the model system. A comprehensive analysis of 18 viral proteins recognized by CD8(+) T cell responses demonstrated that approximately one-fortieth of all possible 9- to 10-mer peptides were high-affinity HLA-A0201 binders. Peptide immunization and T cell recognition data generated from 90 peptides indicated that about one-half of the binders were capable of eliciting T cell responses, and that one-seventh of immunogenic peptides are generated by natural processing. Based on these results, we estimate that vaccinia virus encodes approximately 150 dominant and subdominant epitopes restricted in by HLA-A0201. However, of all these potential epitopes, only 15 are immunodominant and actually recognized in vivo during vaccinia virus infection of HLA-A0201 transgenic mice. Neither peptide-binding affinity, nor complex stability, nor TCR avidity, nor amount of processed epitope appeared to strictly correlate with immunodominance status. Additional experiments suggested that vaccinia infection impairs the development of responses directed against subdominant epitopes. This suggested that additional factors, including immunoregulatory mechanisms, restrict the repertoire of T cell specificities after vaccinia infection by a factor of at least 10.
在对复杂病毒的免疫反应中，许多因素都对免疫显性起作用，但其相对重要性尚不清楚。本研究以痘苗病毒和HLA - A0201作为模型系统来解决这一问题。对CD8(+) T细胞反应所识别的18种病毒蛋白进行全面分析表明，所有可能的9至10聚体肽中约四十分之一是高亲和力的HLA - A0201结合肽。由90种肽产生的肽免疫和T细胞识别数据表明，约一半的结合肽能够引发T细胞反应，且七分之一的免疫原性肽是由天然加工产生的。基于这些结果，我们估计痘苗病毒编码约150个受HLA - A0201限制的显性和亚显性表位。然而，在所有这些潜在表位中，只有15个是免疫显性的，并且在HLA - A0201转基因小鼠感染痘苗病毒期间在体内实际被识别。肽结合亲和力、复合物稳定性、TCR亲和力或加工表位的量似乎都与免疫显性状态没有严格的相关性。额外的实验表明，痘苗病毒感染会损害针对亚显性表位的反应的发展。这表明包括免疫调节机制在内的其他因素将痘苗病毒感染后T细胞特异性的库限制了至少10倍。
