Pretti Marco Antônio M, Vieira Gustavo Fioravanti, Boroni Mariana, Bonamino Martín H
Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil.
Program of Cell and Gene Therapy, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, Brazil.
Brief Bioinform. 2024 Nov 22;26(1). doi: 10.1093/bib/bbaf012.
Antigen recognition by CD8+ T-cell receptors (TCR) is crucial for immune responses to pathogens and tumors. TCRs are cross-reactive, a single TCR can recognize multiple peptide-Human Leukocyte Antigen (HLA) complexes. The study of cross-reactivity can support the development of therapies focusing on immune modulation, such as the expansion of pre-existing T-cell clones to fight pathogens and tumors. The peptide-HLA (pHLA) surface has previously been used to identify TCR cross-reactivities. In the present work, we sought to perform a comprehensive analysis of peptide-HLA by selecting thousands of human and viral epitopes. We profit from established docking models to identify features from different spatial perspectives of HLA-A*02:01, explore similarities between self and non-self epitopes, and list potential cross-reactive epitopes of therapeutic interest. A total of 2631 unique epitopes from representative viral proteins or human proteins were modeled. We were able to demonstrate that cross-reactive CDR3 sequences from public databases recognize epitopes with similar electrostatic potential, charge, and spatial location. Using data from published studies that measured T-cell reactivity to mutated epitopes, we observed a negative correlation between epitope dissimilarity and T-cell activation. Most analysed cancer epitopes were more similar to self epitopes, yet we identified features distinguishing those more similar to viral antigens. Finally, we enumerated potential cross-reactivities between tumoral and viral epitopes and highlighted some challenges in their identification for therapeutic use. Moreover, the thousands of peptide-HLA complexes generated in our work constitute a valuable resource to study T-cell cross-reactivity.
CD8 + T细胞受体（TCR）对病原体和肿瘤的免疫反应至关重要。TCR具有交叉反应性，单个TCR可以识别多种肽 - 人类白细胞抗原（HLA）复合物。交叉反应性的研究有助于开发以免疫调节为重点的疗法，例如扩增预先存在的T细胞克隆以对抗病原体和肿瘤。肽 - HLA（pHLA）表面先前已被用于识别TCR交叉反应性。在本研究中，我们试图通过选择数千个人类和病毒表位来对肽 - HLA进行全面分析。我们利用已建立的对接模型从HLA - A*02:01的不同空间角度识别特征，探索自身和非自身表位之间的相似性，并列出具有治疗意义的潜在交叉反应表位。共对来自代表性病毒蛋白或人类蛋白的2631个独特表位进行了建模。我们能够证明，来自公共数据库的交叉反应性CDR3序列识别具有相似静电势、电荷和空间位置的表位。利用已发表研究中测量T细胞对突变表位反应性的数据，我们观察到表位差异与T细胞活化之间呈负相关。大多数分析的癌症表位与自身表位更相似，但我们确定了那些与病毒抗原更相似的表位的区别特征。最后，我们列举了肿瘤和病毒表位之间的潜在交叉反应性，并强调了在将其鉴定用于治疗时面临的一些挑战。此外，我们工作中生成的数千个肽 - HLA复合物构成了研究T细胞交叉反应性的宝贵资源。
