Pion S, Fontaine P, Desaulniers M, Jutras J, Filep J G, Perreault C
Department of Medicine, University of Montréal, Canada.
Eur J Immunol. 1997 Feb;27(2):421-30. doi: 10.1002/eji.1830270212.
Although there are numerous minor histocompatibility antigens (MiHA), T cell responses leading to graft-versus-host (GVH) and graft-versus-tumor effects involve only a small number of immunodominant MiHA. The goal of the present study was to analyze at the cellular and molecular levels the mechanisms responsible for MiHA immunodominance. Cytotoxic T lymphocytes (CTL) generated in eight combinations of H2b strains of mice were tested against syngeneic targets sensitized with HPLC-fractionated peptides eluted from immunizing cells. The number of dominant MiHA was found to range from as little as two up to ten depending on the strain combination used. The nature of dominant MiHA was influenced by both the antigen profile of the antigen-presenting cells (APC) and the repertoire of responding CTL. When C57BL/6 dominant MiHA (B6dom) and H-Y were presented on separate APC, they showed similar immunogenicity. In contrast, when they were presented on the same APC, B6dom MiHA totally dominated H-Y. B6dom MiHA did not suppress anti-H-Y responses by acting as T cell receptor antagonists for anti-H-Y CTL, nor were anti-B6dom CTL precursors more abundant than anti-H-Y CTL precursors. Dominance resulted from competition for the APC surface between anti-B6dom and anti-H-Y CTL; the crucial difference between the dominant and the dominated MiHA appears to depend on the differential avidity of their respective CTL for APC. The only B6dom epitope thus far identified is the nonapeptide AAPDNRETF presented by H2-D(b). We found that compared with other known D(b)-binding peptides, AAPDNRETF is expressed at very high levels on the cell surface, binds to the D(b) molecule with very high affinity, and dissociates very slowly from its presenting class I molecule. These data indicate that one cannot predict which MiHA will be dominant or dominated based simply on their respective immunogenicity when presented on separate APC. Indeed, the avidity of T cell/APC interactions appears to determine which antigen(s) will trigger T cell responses when numerous epitopes are presented by the same APC.
尽管存在众多次要组织相容性抗原（MiHA），但导致移植物抗宿主（GVH）和移植物抗肿瘤效应的T细胞反应仅涉及少数免疫显性MiHA。本研究的目的是在细胞和分子水平上分析负责MiHA免疫显性的机制。用从免疫细胞洗脱的经高效液相色谱分离的肽致敏的同基因靶细胞，检测在八种H2b小鼠品系组合中产生的细胞毒性T淋巴细胞（CTL）。根据所使用的品系组合，发现显性MiHA的数量范围从少至两个到多达十个。显性MiHA的性质受抗原呈递细胞（APC）的抗原谱和反应性CTL库的影响。当C57BL/6显性MiHA（B6dom）和H-Y在单独的APC上呈递时，它们显示出相似的免疫原性。相反，当它们在同一APC上呈递时，B6dom MiHA完全主导H-Y。B6dom MiHA不会通过作为抗H-Y CTL的T细胞受体拮抗剂来抑制抗H-Y反应，抗B6dom CTL前体也不比抗H-Y CTL前体更丰富。优势来自抗B6dom和抗H-Y CTL之间对APC表面的竞争；显性和非显性MiHA之间的关键差异似乎取决于它们各自的CTL对APC的不同亲和力。迄今为止鉴定出的唯一B6dom表位是由H2-D(b)呈递的九肽AAPDNRETF。我们发现，与其他已知的D(b)结合肽相比，AAPDNRETF在细胞表面以非常高的水平表达，以非常高的亲和力与D(b)分子结合，并且从其呈递的I类分子上解离非常缓慢。这些数据表明，当在单独的APC上呈递时，不能仅仅根据它们各自的免疫原性来预测哪些MiHA将是显性或非显性的。实际上，当同一APC呈递众多表位时，T细胞/APC相互作用的亲和力似乎决定了哪些抗原将触发T细胞反应。
