Gupta Sagar, Sgourakis Nikolaos G
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Structure. 2025 Jul 15. doi: 10.1016/j.str.2025.06.011.
Peptides presented by major histocompatibility complex class I (MHC-I) proteins provide biomarkers for therapeutic targeting using T cell receptors (TCRs), TCR-mimicking antibodies (TMAs), or other engineered protein binders. Despite the extreme sequence diversity of the human leukocyte antigen (HLA, the human MHC), a given TCR or TMA is restricted to recognize epitopic peptides in the context of a limited set of different HLA alleles. Here, guided by our analysis of 98 TCR:pHLA complex structures, we identify TCR contact residues and classify 148 common HLA alleles into T cell cross-reactivity groups (T-CREGs) on the basis of their presented surface features. Insights from our work have actionable value for predicting MHC-I restriction of TCRs, guiding therapeutic expansion of existing TCR-based approaches and informing the selection of peptide targets for the development of new therapeutics.
主要组织相容性复合体I类（MHC-I）蛋白呈递的肽段可为使用T细胞受体（TCR）、TCR模拟抗体（TMA）或其他工程化蛋白结合物进行治疗靶向提供生物标志物。尽管人类白细胞抗原（HLA，即人类MHC）的序列具有极端多样性，但给定的TCR或TMA仅限于在一组有限的不同HLA等位基因背景下识别表位肽段。在此，在对98个TCR:pHLA复合体结构进行分析的指导下，我们确定了TCR接触残基，并根据其呈现的表面特征将148个常见HLA等位基因分类为T细胞交叉反应性组（T-CREG）。我们工作的见解对于预测TCR的MHC-I限制性、指导现有基于TCR方法的治疗性扩展以及为开发新疗法选择肽段靶点具有实际应用价值。
