Pymm Phillip, Illing Patricia T, Ramarathinam Sri H, O'Connor Geraldine M, Hughes Victoria A, Hitchen Corinne, Price David A, Ho Bosco K, McVicar Daniel W, Brooks Andrew G, Purcell Anthony W, Rossjohn Jamie, Vivian Julian P
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
Nat Struct Mol Biol. 2017 Apr;24(4):387-394. doi: 10.1038/nsmb.3381. Epub 2017 Feb 20.
Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.
主要组织相容性复合体I类（MHC-I）分子通过捕获肽段以呈递给T细胞和自然杀伤（NK）细胞，在免疫过程中发挥关键作用。肽段的末端锚定在MHC-I抗原结合槽内，但其他呈递模式是否存在尚不清楚。在此，我们表明，HLA-B57:01肽库的20%由N端延伸集组成，其特征是在第1位（P1）至第2位存在一个共同基序。呈递N端延伸肽段的HLA-B57:01的结构，包括免疫优势HIV-1 Gag表位TW10（TSTLQEQIGW），显示N端从肽结合槽中突出。常见的逃逸突变体TSNLQEQIGW以典型方式结合HLA-B57:01，其构象与TW10肽段截然不同。这影响了NK细胞上表达的杀伤细胞免疫球蛋白样受体（KIR）3DL1的识别。因此，我们定义了人类白细胞抗原I类（HLA-I）免疫肽组中一个以前未被表征的特征，这对病毒免疫逃逸具有影响。我们进一步表明，对HLA-B57:01 - TW10表位的识别受适应性和先天性免疫系统之间“分子张力”的支配。
