Identification of HLA class II restricted determinants of Mycobacterium tuberculosis-derived proteins by using HLA-transgenic, class II deficient mice
Identification of HLA class II restricted determinants of Mycobacterium tuberculosis-derived proteins by using HLA-transgenic, class II deficient mice
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DOI：
10.1073/pnas.95.18.10797
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发表时间：
1998-09-01
影响因子：
11.1
通讯作者：
Ottenhoff, THM
中科院分区：
文献类型：
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作者：
Geluk, A;Taneja, V;Ottenhoff, THM
辅助性T细胞1在针对分枝杆菌病原体的保护性免疫中起主要作用。由于CD 4（+）人T细胞的抗原（Ag）特异性受到HLA II类多态性的强烈控制，因此需要在HLA多态性的背景下定义候选Ag的免疫原性潜力。我们利用了II类缺陷（Ab（0））小鼠，HLA-DR/B1*0301（DR 3）或HLA-DQB 1 *0302/DQA*0301（DQ 8）等位基因的转基因。在这些动物中，所有的CD 4 + T细胞都受到HLA分子的限制。我们以前报道过，人DR 3限制性T细胞经常识别结核分枝杆菌的热休克蛋白（HSP）65，只有一个单一的HSP 65表位，p1-20。用卡介苗或hsp 65免疫的DR3.Ab（0）小鼠产生了对M.结核病，并识别相同的hsp 65表位，p1-20。Hsp 65免疫的DQ8.Ab（0）小鼠对卡介苗产生强烈应答，但对p1-20没有。相反，我们在区域171-200、311-340和411-440中鉴定了三个新的DQ 8限制性T细胞表位。DR3.Ab（0）小鼠用第二种主要M.结核蛋白Ag 85（由85 A、85 B和85 C组成）也仅针对本研究中鉴定的一个决定簇85 B p51-70产生T细胞应答。重要的是，随后对人类T细胞应答的分析显示，HLA-DR 3+、Ag 85反应性个体识别与DR3.Ab（0）小鼠完全相同的肽表位。引人注目的是，DR 3限制性T细胞表位代表了hsp 65和85 B中最好的DR 3结合序列，揭示了肽免疫显性和HLA结合亲和力之间的强烈关联。用免疫优势肽p1-20和p51-70免疫DR3.Ab（0）诱导T细胞对M.结核因此，对于两种不同的Ag，来自DR3.Ab（0）小鼠和HLA-DR 3+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转基因小鼠在识别人类T细胞决定簇的设计新的疫苗。
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 (Ab(0)) mice, transgenic for either HLA-DRA/B1*0301 (DR3) or HLA-DQB1*0302/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.Ab(0) mice, immunized with bacillus Calmette-Guerin or hsp65, developed T cell responses to M. tuberculosis, and recognized the same hsp65 epitope, p1-20. Hsp65-immunized DQ8.Ab(0) mice mounted a strong response to bacillus Calmette-Guerin 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.Ab(0) 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.Ab(0) 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.Ab(0) 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.Ab(0) 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.