Identification of Db- and Kb-restricted subdominant cytotoxic T-cell responses in lymphocytic choriomeningitis virus-infected mice
Identification of Db- and Kb-restricted subdominant cytotoxic T-cell responses in lymphocytic choriomeningitis virus-infected mice
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DOI：
10.1006/viro.1997.8934
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发表时间：
1998-01-05
期刊：
影响因子：
3.7
通讯作者：
Ahmed, R
中科院分区：
文献类型：
--
作者：
van der Most, RG;Murali-Krishna, K;Ahmed, R
抗病毒细胞毒性T细胞对于控制小鼠淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染至关重要。在H - 2(b)小鼠中，抗病毒反应针对病毒核蛋白（NP396 - 404）和糖蛋白（GP276 - 286以及GP33 - 41）中的三个受D - b限制的表位。我们目前的数据揭示了这三个表位之间存在明显的等级关系，其中NP396 - 404具有免疫优势，其次分别是GP33 - 41和GP276 - 286。为了在LCMV核蛋白和糖蛋白中鉴定其他细胞毒性T淋巴细胞（CTL）表位，我们利用了D - b和K - b结合肽的基序，并结合了主要组织相容性复合体（MHC）I类结合试验。在23个符合D - b基序的肽中，我们鉴定出4个D - b结合物，其中一个（GP92 - 101）被证明是一个新的CTL表位。在28个符合K - b基序的肽中，12个与K - b结合，其中一个（NP205 - 212）是一个CTL表位。这两个新鉴定的CTL肽在体外二次刺激后均可被LCMV免疫的脾细胞识别。这两个肽都以中等亲和力与其MHC I类分子结合（GP92 - 101和NP205 - 212分别为470和170 nM）。针对这些肽的反应比对三个主要表位的反应弱。高亲和力结合物都不是新表位，这表明高亲和力结合物要么是免疫优势表位，要么根本不是表位。因此，对51个符合K - b和D - b基序的肽进行分析，得到了2个新的、次优势表位。用这些肽或用表达这些表位作为小基因的痘苗病毒重组体对C57BL/6小鼠进行免疫，可预防慢性LCMV感染，这表明用次优势表位进行免疫可赋予对慢性病毒感染的保护作用。（C）1998年学术出版社
Antiviral cytotoxic T-cells are critical for control of lymphoctytic choriomeningitis virus (LCMV) infection in mice. In H-2(b) mice, the antiviral response is directed against three D-b-restricted epitopes in the viral nucleoprotein (NP396-404) and glycoprotein (GP276-286 and GP33-41). Our present data revealed a clear hierarchy among these three epitopes, in which NP396-404 is immunodominant, followed by GP33-41 and GP276-286, respectively. In order to identify additional CTL epitopes in the LCMV nucleoprotein and glycoprotein, we used the motifs for D-b-and K-b-binding peptides, combined with MHC class I-binding assays. Out of 23 D-b motif-fitting peptides, we identified 4 D-b binders, one of which (GP92-101) turned out to be a new CTL epitope. Among 28 K-b motif-fitting peptides, 12 bound K-b, and one of these (NP205-212) was a CTL epitope. Both newly identified CTL peptides were recognized by LCMV-immune splenocytes after secondary in vitro stimulation. Both peptides bound their MHC class I molecules with intermediate affinity (470 and 170 nM for GP92-101 and NP205-212, respectively). Responses against these peptides were weaker than the responses against the three major epitopes. None of the high affinity binders were new epitopes, suggesting that high affinity binders are either immunodominant epiitopes or no epitopes at all. Thus, analysis of 51 K-b and D-b motif-fitting peptides yielded 2 new, subdominant epitopes. Immunization of C57BL/6 mice with these peptides, or with vaccinia virus recombinants expressing these epitopes as minigenes, protected against chronic LCMV infection, demonstrating that immunization with subdominant epitopes can confer protection against chronic viral infection. (C) 1998 Academic Press.