Chunyu Wang

All Publications

• Deep peptide recognition profiling decodes TCR specificity and enables disease-associated antigen discovery. Nature biotechnology Wang, N., Yeh, H., Lai, B., Perera, J., Jude, K. M., Risch, I., Um, J., Chen, X., Xiang, X., Wang, C., Liu, L. D., Yang, X., Paley, M. A., Khan, A. A., Garcia, K. C. 2026

  Abstract

  Predicting T cell receptor (TCR) specificity on the basis of sequence is challenging because TCRs of similar sequence can recognize entirely different antigens, whereas TCRs of different sequence can recognize the same antigens. Here we present a system that integrates high-throughput yeast display with fine-tuned protein language models (pLMs) to generate deep peptide recognition profiles (PRPs) for individual TCRs, each detailing binding against millions of peptides. We provide detailed PRPs for a panel of HLA-B*27:05-restricted TCRs from persons with ankylosing spondylitis and acute anterior uveitis that almost exclusively recognize peptides through CDR3β. pLMs trained on these PRPs outperform AlphaFold3 and tFold-TCR in predicting T cell activation. We discover and validate novel candidate autoantigens, demonstrate that model generalization to new TCRs correlates with functional distance (PRP divergence) rather than sequence similarity and introduce a model-intrinsic uncertainty metric to quantify prediction confidence. This system and its associated PRP datasets offer a scalable approach to mapping TCR recognition, accelerating antigen discovery and guiding TCR engineering.

  View details for DOI 10.1038/s41587-026-03128-x

  View details for PubMedID 42129507

  View details for PubMedCentralID 3474532

• Design of solubly expressed miniaturized SMART MHCs. Proceedings of the National Academy of Sciences of the United States of America White, W. L., Bai, H., Kim, C. J., Jude, K. M., Sun, R., Guerrero, L., Han, X., Chen, X., Chaudhuri, A., Bonzanini, J. E., Sun, Y., Onwuka, A. E., Wang, N., Wang, C., Nygren, P. Å., Li, X., Goreshnik, I., Allen, A., Levine, P. M., Kueh, H. Y., Jewett, M. C., Sgourakis, N. G., Achour, A., Garcia, K. C., Baker, D. 2026; 123 (1): e2505932123

  Abstract

  The precise recognition of specific peptide-major histocompatibility complex (pMHC) complexes by T cell receptors (TCRs) plays a key role in infectious disease, cancer, and autoimmunity. A critical step in many immunobiological studies is the identification of T cells expressing TCRs specific to a given pMHC antigen. However, the intrinsic instability of empty class-I MHCs limits their soluble expression in Escherichia coli and makes it very difficult to characterize even a small fraction of possible pMHC/TCR interactions. To overcome this limitation, we designed small proteins which buttress the peptide binding groove of class I MHCs, replacing β2-microglobulin (β2m) and the heavy chain α3 domain, and enable soluble and partially soluble expression in E. coli of H-2Db and A*02:01, respectively. We demonstrate that these soluble, monomeric, antigen-receptive, truncated (SMART) MHCs retain both peptide- and TCR-binding specificity and that peptide-bound structures of both allomorphs are similar to their full-length, native counterparts. With extension to the majority of HLA alleles, SMART MHCs should be broadly useful for probing the T cell repertoire in approaches ranging from yeast display to T cell staining.

  View details for DOI 10.1073/pnas.2505932123

  View details for PubMedID 41481462

• Design of high-specificity binders for peptide-MHC-I complexes. Science (New York, N.Y.) Liu, B., Greenwood, N. F., Bonzanini, J. E., Motmaen, A., Meyerberg, J., Dao, T., Xiang, X., Ault, R., Sharp, J., Wang, C., Visani, G. M., Vafeados, D. K., Roullier, N., Nourmohammad, A., Scheinberg, D. A., Garcia, K. C., Baker, D. 2025; 389 (6758): 386-391

  Abstract

  Class I major histocompatibility complex (MHC-I) molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance. Proteins that recognize peptide-MHC-I (pMHCI) complexes with specificity for diseased cells could have considerable therapeutic utility. Specificity requires recognition of outward-facing amino acid residues within the disease-associated peptide as well as avoidance of extensive contacts with ubiquitously expressed MHC. We used RFdiffusion to design pMHCI-binding proteins that make extensive contacts with the peptide and identified specific binders for 11 target pMHCs starting from either experimental or predicted pMHCI structures. Upon incorporation into chimeric antigen receptors, designs for eight targets conferred peptide-specific T cell activation. Our approach should have broad utility for both protein- and cell-based pMHCI targeting.

  View details for DOI 10.1126/science.adv0185

  View details for PubMedID 40705892

• Design of high specificity binders for peptide-MHC-I complexes. bioRxiv : the preprint server for biology Liu, B., Greenwood, N. F., Bonzanini, J. E., Motmaen, A., Sharp, J., Wang, C., Visani, G. M., Vafeados, D. K., Roullier, N., Nourmohammad, A., Garcia, K. C., Baker, D. 2024

  Abstract

  Class I MHC molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance, and specific targeting of these peptide-MHC (pMHC) complexes could have considerable utility for treating diseases. Such targeting is challenging as it requires readout of the few outward facing peptide antigen residues and the avoidance of extensive contacts with the MHC carrier which is present on almost all cells. Here we describe the use of deep learning-based protein design tools to denovo design small proteins that arc above the peptide binding groove of pMHC complexes and make extensive contacts with the peptide. We identify specific binders for ten target pMHCs which when displayed on yeast bind the on-target pMHC tetramer but not closely related peptides. For five targets, incorporation of designs into chimeric antigen receptors leads to T-cell activation by the cognate pMHC complexes well above the background from complexes with peptides derived from proteome. Our approach can generate high specificity binders starting from either experimental or predicted structures of the target pMHC complexes, and should be widely useful for both protein and cell based pMHC targeting.

  View details for DOI 10.1101/2024.11.28.625793

  View details for PubMedID 39651227

  View details for PubMedCentralID PMC11623666