Project Reference: TRG27-PAT-RR1

Project title: The antigen specificity of regulatory T cell suppression using TCR-transgenic mouse models

Project outline

Regulatory T (Treg) cells prevent the immune system from attacking our own tissues and harmless substances, yet how they do this without disabling protective immunity is poorly understood. Each Treg carries a T cell receptor (TCR) recognising a specific antigen, but how this specificity directs suppression is unclear. Three models have been proposed for how Treg antigen specificity shapes suppression. In the cognate-restricted model, Tregs suppress only T cells that recognise the same antigen. In the APC-licensing model, Tregs disable the antigen-presenting cell on which they recognise antigen, indirectly suppressing all T cells primed by that cell. In the bystander model, Tregs release signals that dampen any neighbouring T cell regardless of specificity. This project uses TCR-transgenic systems, in which Treg and conventional T cells of defined specificity can be tracked and manipulated, to test directly how Tregs suppress cognate responses. By combining Tregs and Tconv cells of matched or mismatched specificity, with antigens presented on the same or separate APCs, the student will map the antigenic reach of suppression and identify its mechanism.

Objectives: (1) establish co-culture and adoptive-transfer systems using defined TCR-transgenic Treg/Tconv pairs; (2) quantify suppression of matched versus mismatched Tconv responses using pMHC tetramers, high-dimensional flow and TCR-repertoire sequencing; (3) test whether shared antigen presentation is required, discriminating cognate, APC-linked and bystander suppression; (4) define the underlying mechanism, including TCR-driven capture of peptide-MHC using single-cell RNA/TCR seq, imaging and quantitative modelling that links TCR signal strength and antigen load to the mode of suppression. The work will reveal fundamental rules governing antigen-specific immune tolerance and train the student in in vivo immunology, high-dimensional flow cytometry, and computational analysis of single-cell and TCR-repertoire data.

Principal Supervisor

Professor Rahul Roychoudhuri

Email address: rr257@cam.ac.uk

Department / Partner Institute: Pathology

Website:  http://roychoudhurilab.org/

BBSRC strategic theme

Understanding the rules of life