{"ID":2898939,"CreatedAt":"2026-06-01T04:54:23.091178241Z","UpdatedAt":"2026-06-01T04:54:23.091178241Z","DeletedAt":null,"paper_url":"https://arxiv.org/abs/2507.03197","arxiv_id":"2507.03197","title":"Quantifying Cross-Attention Interaction in Transformers for Interpreting TCR-pMHC Binding","abstract":"CD8+ \"killer\" T cells and CD4+ \"helper\" T cells play a central role in the adaptive immune system by recognizing antigens presented by Major Histocompatibility Complex (pMHC) molecules via T Cell Receptors (TCRs). Modeling binding between T cells and the pMHC complex is fundamental to understanding basic mechanisms of human immune response as well as in developing therapies. While transformer-based models such as TULIP have achieved impressive performance in this domain, their black-box nature precludes interpretability and thus limits a deeper mechanistic understanding of T cell response. Most existing post-hoc explainable AI (XAI) methods are confined to encoder-only, co-attention, or model-specific architectures and cannot handle encoder-decoder transformers used in TCR-pMHC modeling. To address this gap, we propose Quantifying Cross-Attention Interaction (QCAI), a new post-hoc method designed to interpret the cross-attention mechanisms in transformer decoders. Quantitative evaluation is a challenge for XAI methods; we have compiled TCR-XAI, a benchmark consisting of 274 experimentally determined TCR-pMHC structures to serve as ground truth for binding. Using these structures we compute physical distances between relevant amino acid residues in the TCR-pMHC interaction region and evaluate how well our method and others estimate the importance of residues in this region across the dataset. We show that QCAI achieves state-of-the-art performance on both interpretability and prediction accuracy under the TCR-XAI benchmark.","short_abstract":"CD8+ \"killer\" T cells and CD4+ \"helper\" T cells play a central role in the adaptive immune system by recognizing antigens presented by Major Histocompatibility Complex (pMHC) molecules via T Cell Receptors (TCRs). Modeling binding between T cells and the pMHC complex is fundamental to understanding basic mechanisms of...","url_abs":"https://arxiv.org/abs/2507.03197","url_pdf":"https://arxiv.org/pdf/2507.03197v3","authors":"[\"Jiarui Li\",\"Zixiang Yin\",\"Haley Smith\",\"Zhengming Ding\",\"Samuel J. Landry\",\"Ramgopal R. Mettu\"]","published":"2025-07-03T22:18:54Z","proceeding":"cs.CE","tasks":"[\"cs.CE\",\"cs.LG\",\"q-bio.BM\"]","methods":"[\"Transformer\"]","has_code":false}