A large fraction of HLA class I ligands are proteasome-generated spliced peptides

The proteasome generates the epitopes presented on human leukocyte antigen (HLA) class I molecules that elicit CD8+ T cell responses. Reports of proteasome-generated spliced epitopes exist, but they have been regarded as rare events. Here, however, we show that the proteasome-generated spliced peptide pool accounts for one-third of the entire HLA class I immunopeptidome in terms of diversity and one-fourth in terms of abundance. This pool also represents a unique set of antigens, possessing particular and distinguishing features. We validated this observation using a range of complementary experimental and bioinformatics approaches, as well as multiple cell types. The widespread appearance and abundance of proteasome-catalyzed peptide splicing events has implications for immunobiology and autoimmunity theories and may provide a previously untapped source of epitopes for use in vaccines and cancer immunotherapy.

蛋白酶体（proteasome）可产生呈递于人类白细胞抗原（human leukocyte antigen，缩写HLA）I类分子上的表位，此类表位可诱发CD8+ T细胞应答。已有研究报道过由蛋白酶体产生的剪接型表位，但此类表位曾被认为是罕见事件。然而本研究表明，蛋白酶体催化产生的剪接肽库在多样性层面占整个HLA I类免疫肽组的三分之一，在丰度层面则占四分之一。此类肽库同时代表一类独特的抗原集合，具备特定且鲜明的特征。本研究通过一系列互补的实验与生物信息学方法，结合多种细胞类型对该观察结果进行了验证。蛋白酶体催化的肽剪接事件的广泛存在与高丰度，对免疫生物学及自身免疫理论具有重要启示，同时或可成为疫苗研发与癌症免疫治疗中尚未被发掘的表位来源。