AI/ML-Empowered Approaches for Predicting T Cell-Mediated Immunity and Beyond

Authors

Cheng-Chi Chao
Yulun Chiu
Lucas Yeung
Cassian Yee
Chongming Jiang
Xiling Shen

Publication Date

1-1-2025

Journal

Frontiers in Immunology

DOI

10.3389/fimmu.2025.1651533

PMID

40948755

PMCID

PMC12426251

PubMedCentral® Posted Date

8-29-2025

PubMedCentral® Full Text Version

Post-print

Abstract

T cells play a dual role in various physiopathological states, capable of eliminating tumors and infected cells, while also playing a pathogenic role when activated by autoantigens, causing self-tissue damage. The regulation of T cell-peptide/major histocompatibility complex (TCR-pMHC) recognition is crucial for maintaining disease balance and treating cancer, infections, and autoimmune diseases. Despite efforts, predictive models of TCR-pMHC specificity are still in the early stages. Inspired by advances in protein structure prediction via deep neural networks, we evaluated AlphaFold 3 (AF3)-based AI computation as a method to predict TCR epitope specificity. We demonstrate that AlphaFold can model TCR-pMHC interactions, distinguishing valid epitopes from invalid ones with increasing accuracy. Immunogenic epitopes can be identified for vaccine development through in silico high-throughput processes. Additionally, higher-affinity and specific T cells can be designed to enhance therapy efficacy and safety. An accurate TCR-pMHC prediction model is expected to greatly benefit T-cell-mediated immunotherapy and aid drug design. Overall, precise prediction of T-cell immunogenicity holds significant therapeutic potential, allowing the identification of peptide epitopes linked to tumors, infections, and autoimmune diseases. Although there is much work to be done before these predictions achieve widespread practical use, we are optimistic that deep learning-based structural modeling is a promising pathway for the generalizable prediction of TCR-pMHC interactions.

Keywords

TCR-pMHC recognition, AI/ML-driven structure prediction, immunogenicity modeling, T-cell therapy design, protein-protein interactions

Published Open-Access

yes

Recommended Citation

Chao, Cheng-Chi; Chiu, Yulun; Yeung, Lucas; et al., "AI/ML-Empowered Approaches for Predicting T Cell-Mediated Immunity and Beyond" (2025). Faculty, Staff and Student Publications. 5053.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5053