# Quantifying Cross-Attention Interaction in Transformers for Interpreting TCR-pMHC Binding

arXiv: https://arxiv.org/abs/2507.03197 · HTML: https://mlsanity.com/paper/2507.03197/

## Key facts

- Cited by 4 papers in the map (data through 14 Oct 2026).
- Builds on 17 of its 82 references that are in the map.
- First posted on arXiv 3 Jul 2025.

## Builds on (most cited first, 17 of 17)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [BERT: Pre-training of Deep Bidirectional Transformers for Language Understanding](https://mlsanity.com/paper/1810.04805/) (2018)
- [Learning Transferable Visual Models From Natural Language Supervision](https://mlsanity.com/paper/2103.00020/) (2021)
- [Microsoft COCO: Common Objects in Context](https://mlsanity.com/paper/1405.0312/) (2014)
- [Grad-CAM: Visual Explanations from Deep Networks via Gradient-based Localization](https://mlsanity.com/paper/1610.02391/) (2016)
- [Learning Deep Features for Discriminative Localization](https://mlsanity.com/paper/1512.04150/) (2015)
- [Grad-CAM++: Improved Visual Explanations for Deep Convolutional Networks](https://mlsanity.com/paper/1710.11063/) (2017)
- [Analyzing Multi-Head Self-Attention: Specialized Heads Do the Heavy Lifting, the Rest Can Be Pruned](https://mlsanity.com/paper/1905.09418/) (2019)
- [Quantifying Attention Flow in Transformers](https://mlsanity.com/paper/2005.00928/) (2020)
- [Attention is not not Explanation](https://mlsanity.com/paper/1908.04626/) (2019)
- [Generic Attention-model Explainability for Interpreting Bi-Modal and Encoder-Decoder Transformers](https://mlsanity.com/paper/2103.15679/) (2021)
- [Layer-wise Relevance Propagation for Neural Networks with Local Renormalization Layers](https://mlsanity.com/paper/1604.00825/) (2016)
- [AttnLRP: Attention-Aware Layer-Wise Relevance Propagation for Transformers](https://mlsanity.com/paper/2402.05602/) (2024)
- [XAI for Transformers: Better Explanations through Conservative Propagation](https://mlsanity.com/paper/2202.07304/) (2022)
- [Token Transformation Matters: Towards Faithful Post-hoc Explanation for Vision Transformer](https://mlsanity.com/paper/2403.14552/) (2024)
- [TITAN: T Cell Receptor Specificity Prediction with Bimodal Attention Networks](https://mlsanity.com/paper/2105.03323/) (2021)
- [Sequence-Only Prediction of Binding Affinity Changes: A Robust and Interpretable Model for Antibody Engineering](https://mlsanity.com/paper/2505.20301/) (2025)

## Built on by (most cited first, 4 of 4)

- [TCR-EML: Explainable Model Layers for TCR-pMHC Prediction](https://mlsanity.com/paper/2510.04377/) (2025)
- [Structure-Regularized Interpretable TCR-Epitope Prediction](https://mlsanity.com/paper/2606.30902/) (2026)
- [Why Does It Look There? Structured Explanations for Image Classification](https://mlsanity.com/paper/2603.10234/) (2026)
- [Explainability from Training with Applications to TCR-Epitope Prediction](https://mlsanity.com/paper/2609.36354/) (2026)

## Abstract (arXiv)

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.