Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology (GBB) Institute, University of Groningen, Groningen, Netherlands.
Front Immunol. 2022 Jan 11;12:763044. doi: 10.3389/fimmu.2021.763044. eCollection 2021.
Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most alleles of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefore peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the predicted over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II, and confirmed by re-analysis of epitope databases. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells are more tuned to respond to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs are less prone to mutations that enable pathogens to evade T cell responses.
细胞毒性 T 细胞反应预计偏向于膜蛋白。大多数主要组织相容性复合体 I（MHC-I）等位基因的肽结合槽相对疏水，因此衍生自人类跨膜螺旋（TMH）的肽片段预计会更频繁地被呈递，这与它们在蛋白质组中的丰度相符。然而，膜蛋白可能过度呈现的生理原因尚不清楚。在这项研究中，我们表明，TMH 衍生肽的过度预测是普遍的，既适用于细菌和病毒，也适用于 MHC-I 和 MHC-II，并通过对表位数据库的重新分析得到了证实。此外，我们表明 TMHs 在进化上更保守，因为与编码细胞外和细胞质蛋白区域的染色体区域相比，TMH 编码区域中的单核苷酸多态性（SNP）出现的频率相对较低。因此，我们的研究结果表明，细胞毒性 T 细胞和辅助 T 细胞对膜蛋白的反应更为敏感，因为这些蛋白在进化上更为保守。我们推测，TMHs 不太容易发生突变，从而使病原体逃避 T 细胞的反应。
