Geluk A, Taneja V, van Meijgaarden K E, Zanelli E, Abou-Zeid C, Thole J E, de Vries R R, David C S, Ottenhoff T H
Department of Immunohematology and Blood Bank, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10797-802. doi: 10.1073/pnas.95.18.10797.
T helper 1 cells play a major role in protective immunity against mycobacterial pathogens. Since the antigen (Ag) specificity of CD4(+) human T cells is strongly controlled by HLA class II polymorphism, the immunogenic potential of candidate Ags needs to be defined in the context of HLA polymorphism. We have taken advantage of class II-deficient (Ab0) mice, transgenic for either HLA-DRA/B10301 (DR3) or HLA-DQB10302/DQA*0301 (DQ8) alleles. In these animals, all CD4(+) T cells are restricted by the HLA molecule. We reported previously that human DR3-restricted T cells frequently recognize heat shock protein (hsp)65 of Mycobacterium tuberculosis, and only a single hsp65 epitope, p1-20. DR3.Ab0 mice, immunized with bacillus Calmette-Guérin or hsp65, developed T cell responses to M. tuberculosis, and recognized the same hsp65 epitope, p1-20. Hsp65-immunized DQ8.Ab0 mice mounted a strong response to bacillus Calmette-Guérin but not to p1-20. Instead, we identified three new DQ8-restricted T cell epitopes in the regions 171-200, 311-340, and 411-440. DR3.Ab0 mice immunized with a second major M. tuberculosis protein, Ag85 (composed of 85A, 85B, and 85C), also developed T cell responses against only one determinant, 85B p51-70, that was identified in this study. Importantly, subsequent analysis of human T cell responses revealed that HLA-DR3+, Ag85-reactive individuals recognize exactly the same peptide epitope as DR3.Ab0 mice. Strikingly, both DR3-restricted T cell epitopes represent the best DR3-binding sequences in hsp65 and 85B, revealing a strong association between peptide-immunodominance and HLA binding affinity. Immunization of DR3.Ab0 with the immunodominant peptides p1-20 and p51-70 induced T cell reactivity to M. tuberculosis. Thus, for two different Ags, T cells from DR3.Ab0 mice and HLA-DR3+ humans recognize the same immunodominant determinants. Our data support the use of HLA-transgenic mice in identifying human T cell determinants for the design of new vaccines.
辅助性T细胞1在抗分枝杆菌病原体的保护性免疫中起主要作用。由于CD4(+)人T细胞的抗原（Ag）特异性受HLA II类多态性的强烈控制，候选抗原的免疫原性潜力需要在HLA多态性的背景下确定。我们利用了II类缺陷（Ab0）小鼠，它们分别转染了HLA-DRA/B10301（DR3）或HLA-DQB10302/DQA*0301（DQ8）等位基因。在这些动物中，所有CD4(+) T细胞都受HLA分子的限制。我们之前报道过人DR3限制的T细胞经常识别结核分枝杆菌的热休克蛋白（hsp）65，且只有一个hsp65表位，即p1-20。用卡介苗或hsp65免疫的DR3.Ab0小鼠产生了针对结核分枝杆菌的T细胞反应，并识别相同的hsp65表位p1-20。用hsp65免疫的DQ8.Ab0小鼠对卡介苗产生了强烈反应，但对p1-20没有反应。相反，我们在171-200、311-340和411-440区域鉴定出三个新的DQ8限制的T细胞表位。用结核分枝杆菌的另一种主要蛋白Ag85（由85A、85B和85C组成）免疫的DR3.Ab0小鼠也仅对一个在本研究中鉴定出的决定簇85B p51-70产生了T细胞反应。重要的是，随后对人T细胞反应的分析表明，HLA-DR3+、Ag85反应性个体识别的肽表位与DR3.Ab0小鼠完全相同。引人注目的是，两个DR3限制的T细胞表位都代表hsp65和85B中最佳的DR3结合序列，揭示了肽免疫显性与HLA结合亲和力之间的强关联。用免疫显性肽p1-20和p51-70免疫DR3.Ab0诱导了对结核分枝杆菌的T细胞反应性。因此，对于两种不同的抗原，来自DR3.Ab0小鼠和HLA-DR3+人的T细胞识别相同的免疫显性决定簇。我们的数据支持使用HLA转基因小鼠来鉴定人T细胞决定簇以设计新疫苗。
