Selected HLA-B allotypes are resistant to inhibition or deficiency of the transporter associated with antigen processing (TAP)

Major histocompatibility complex class I (MHC-I) molecules present antigenic peptides to CD8+ T cells, and are also important for natural killer (NK) cell immune surveillance against infections and cancers. MHC-I molecules are assembled via a complex assembly pathway in the endoplasmic reticulum (ER) of cells. Peptides present in the cytosol of cells are transported into the ER via the transporter associated with antigen processing (TAP). In the ER, peptides are assembled with MHC-I molecules via the peptide-loading complex (PLC). Components of the MHC-I assembly pathway are frequently targeted by viruses, in order to evade host immunity. Many viruses encode inhibitors of TAP, which is thought to be a central source of peptides for the assembly of MHC-I molecules. However, human MHC-I (HLA-I) genes are highly polymorphic, and it is conceivable that several variants can acquire peptides via TAP-independent pathways, thereby conferring resistance to pathogen-derived inhibitors of TAP. To broadly assess TAP-independent expression within the HLA-B locus, expression levels of 27 frequent HLA-B alleles were tested in cells with deficiencies in TAP. Approximately 15% of tested HLA-B allotypes are expressed at relatively high levels on the surface of TAP1 or TAP2-deficient cells and occur in partially peptide-receptive forms and Endoglycosidase H sensitive forms on the cell surface. Synergy between high peptide loading efficiency, broad specificity for peptides prevalent within unconventional sources and high intrinsic stability of the empty form allows for deviations from the conventional HLA-I assembly pathway for some HLA-B*35, HLA-B*57 and HLA-B*15 alleles. Allotypes that display higher expression in TAP-deficient cells are more resistant to viral TAP inhibitor-induced HLA-I down-modulation, and HLA-I down-modulation-induced NK cell activation. Thus, unconventional antigen presentation pathways are broadly prevalent among HLA-B allotypes, and provide mechanisms to counter pathogen evasion strategies that target the conventional TAP-dependent HLA-I assembly pathway.

主要组织相容性复合体I类（Major histocompatibility complex class I, MHC-I）分子可将抗原肽呈递给CD8+ T细胞，同时在自然杀伤（natural killer, NK）细胞针对感染与癌症的免疫监视过程中发挥重要作用。MHC-I分子在细胞的内质网（endoplasmic reticulum, ER）中通过复杂的组装通路完成组装。存在于细胞胞质中的肽段可通过抗原加工相关转运体（transporter associated with antigen processing, TAP）转运至内质网内。在内质网中，肽段可通过肽加载复合物（peptide-loading complex, PLC）与MHC-I分子结合组装。病毒常会靶向MHC-I组装通路的各类组分，以此逃避宿主的免疫防御。众多病毒会编码TAP的抑制剂，而TAP被认为是为MHC-I分子组装提供肽段的核心来源。不过，人类MHC-I（HLA-I）基因具有高度多态性，因此可以推测，部分等位基因变异体可通过不依赖TAP的途径获取肽段，进而获得对病原体来源TAP抑制剂的抗性。为全面评估HLA-B基因座内不依赖TAP的表达情况，研究人员在TAP缺陷的细胞中检测了27种常见HLA-B等位基因的表达水平。检测结果显示，约15%的被测HLA-B异型在TAP1或TAP2缺陷细胞的表面呈现较高水平的表达，且以部分肽结合型与内切糖苷酶H（Endoglycosidase H）敏感形式存在于细胞表面。对于部分HLA-B*35、HLA-B*57及HLA-B*15等位基因而言，高肽加载效率、对非常规来源优势肽段的广泛结合特异性，以及空态形式较高的内在稳定性三者的协同作用，使其能够偏离常规的HLA-I组装通路。在TAP缺陷细胞中表达水平更高的HLA-B异型，对病毒TAP抑制剂诱导的HLA-I下调，以及HLA-I下调引发的NK细胞活化，均具有更强的抗性。综上，非常规抗原呈递通路在HLA-B异型中广泛存在，可为对抗那些靶向常规依赖TAP的HLA-I组装通路的病原体免疫逃避策略提供应对机制。