COI Project 3: Structural Mechanisms of T Cell Receptor Recognition of Peptide Antigen via pMHC Complexes

About the Project

Immune surveillance is critical for eliminating cancer cells and cells infected with viruses. Central to this process is the interaction between the T cell receptor (TCR) on T cells and peptide–major histocompatibility complex (pMHC) molecules on target cells. The biochemical and structural features of TCR–pMHC engagement dictate the immune response, yet the fundamental rules governing TCR specificity and sensitivity remain poorly understood.

This project will use cryo-electron microscopy (cryoEM) and structural biology to define the structural “fingerprints” of productive TCR–pMHC interactions that drive T cell activation. We have recently made a key technical breakthrough and determined the first high-resolution structures of native, unmodified TCR–pMHC complexes from SARS-CoV2–infected individuals, despite their low affinity and conformational flexibility. This advance establishes a robust cryoEM pipeline to characterize native TCRs—tumour-reactive or pathogen-specific—in complex with natural pMHCs.

We will compare diverse complexes to identify conserved features and structural variations linked to specificity, sensitivity, and affinity using recombinant protein complexes. We will further advance this work to native TCR/CD3–pMHC assemblies in the context of membranes, as formed within the immunological synapse, using in situ cryo-electron tomography.

These studies will uncover the molecular basis of TCR recognition and provide critical insights for selecting TCRs with optimal specificity and safety for TCR-based immunotherapies.

Supervisors

1. Prof. Peijun Zhang
2. Dr. Ricardo A. Fernandes

Funding

The Nuffield Department of Medicine (NDM) is one of the largest and most highly regarded departments of medicine in Europe and noted for the wide range and excellence of its basic and clinical research.

The CAMS Oxford Institute is embedded within NDM, and has two fully-funded DPhil Studentships on offer for the 2026 student intake, supported by funding from COI and AbbVie