Kløverpris Henrik N, McGregor Reuben, McLaren James E, Ladell Kristin, Harndahl Mikkel, Stryhn Anette, Carlson Jonathan M, Koofhethile Catherine, Gerritsen Bram, Keşmir Can, Chen Fabian, Riddell Lynn, Luzzi Graz, Leslie Alasdair, Walker Bruce D, Ndung'u Thumbi, Buus Søren, Price David A, Goulder Philip J
Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom; Department of International Health, Immunology, and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban 4001, South Africa;
Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
J Immunol. 2015 Jun 1;194(11):5329-45. doi: 10.4049/jimmunol.1400854. Epub 2015 Apr 24.
Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available Ag pool derived from a given pathogen. In the case of CD8(+) T cells, these constrained epitope-targeting patterns are linked to HLA class I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, little is known about the factors that control immunodominance in vivo. In this study, we conducted an extensive analysis of CD8(+) T cell responses restricted by a single HLA class I molecule to evaluate the mechanisms that contribute to epitope-targeting frequency and antiviral efficacy in HIV-1 infection. A clear immunodominance hierarchy was observed across 20 epitopes restricted by HLA-B42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gag-specific responses and targeting breadth were associated with lower viral load set-points. However, peptide-HLA-B42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, immunodominance correlated with epitope-specific usage of public TCRs, defined as amino acid residue-identical TRB sequences that occur in multiple individuals. Collectively, these results provide important insights into a potential link between shared TCR recruitment, immunodominance, and antiviral efficacy in a major human infection.
免疫显性描述了一种现象，即免疫系统始终仅靶向源自特定病原体的可用抗原库的一部分。就CD8(+) T细胞而言，这些受限的表位靶向模式与HLA I类表达相关联，并决定疾病进展。尽管这些预先确定的反应层次结构具有生物学重要性，但对于体内控制免疫显性的因素知之甚少。在本研究中，我们对受单个HLA I类分子限制的CD8(+) T细胞反应进行了广泛分析，以评估促成HIV-1感染中表位靶向频率和抗病毒效力的机制。在受HLA-B42:01限制的20个表位中观察到了明确的免疫显性层次结构，HLA-B42:01在非洲裔人群中高度流行。此外，与先前的研究一致，Gag特异性反应和靶向广度与较低的病毒载量设定点相关。然而，肽-HLA-B*42:01结合亲和力和稳定性与靶向频率没有显著关联。相反，免疫显性与公共TCR的表位特异性使用相关，公共TCR定义为在多个个体中出现的氨基酸残基相同的TRB序列。总体而言，这些结果为主要人类感染中共享TCR募集、免疫显性和抗病毒效力之间的潜在联系提供了重要见解。
