Lymphocyte Antigen Receptor Recognition of Non-Classical Ligands

Project Details:

The rapid implementation of machine learning-based predictive models across biology has been impressive, yet the small number of published T-cell receptor (TCR):epitope pairs (and even smaller number of those that have been functionally validated) remains insufficient to train a reliable, high-performing foundational model. Beyond this, the bias of existing training data toward a fraction of ligand diversity severely compromises the ability of existing models to extrapolate beyond ligands within that space, and many such approaches are hampered by reliance on low-level epitope predictions based on methodologies prone to error and sensitivity issues. The main goal of this project will be to further develop and apply experimental pipelines for TCR de-orphanization and ligand discovery, in particular in two very challenging areas: class II HLA presentation to CD4+ T cells, and post-translationally modified peptide epitopes.

Objective 1 of this project is to identify a small number of disease-relevant, fully human TCR:ligand pairs in which the presented peptide is modified post-translationally. Examples of such PTMs include citrullination, deamidation, and phosphorylation.

In Objective 2, this project will use these pairs as a baseline to screen patient cohorts for TCRs that recognize post-translationally modified ligands, building a functional repertoire and providing substantial evidence for the role of PTM epitopes in driving human lymphocyte responses. Relevant disease models may include autoimmune diabetes, coeliac disease, and rheumatoid arthritis but can also consider protective immune responses, for example in anti-tumour T cell activation.

Objective 3 will link the cellular arm of the adaptive immune system to the humoral arm, expanding to antigen-specific B cell receptors in the context of CD4-mediated lymphocyte responses.

This PhD training will provide an excellent opportunity to develop technical expertise in high-throughput approaches to immune responses, a deep understanding of the antigen-specific mechanisms driving lymphocyte biology, and a practical, translatable perspective on the molecular engineering of cellular systems, including the bioinformatic analysis of large data sets in a computational setting.

Person Specification

Applicants should have a strong background in Cell and Molecular Biology, and ideally a background in Molecular Immunology or Lymphocyte Biology. They should have a commitment to research in Immuno-oncology and/or Autoimmunity and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply

Informal enquiries should be directed to John M. Lindner

Applications should be directed to John M. Lindner (email j.m.lindner@bham.ac.uk). To apply, please send:

•  A detailed CV, including your nationality and country of birth;

•  Names and addresses of two referees;

•  A covering letter highlighting your research experience/capabilities;

•  Copies of your degree certificates with transcripts;

•  Evidence of your proficiency in the English language, if applicable.