Project Reference: TRG27-SCI-ST1

Project title: Mapping the rules of barrier tolerance in the gut 

Project outline

Barrier surfaces such as the gut, skin and lungs host dense microbial communities in symbiosis, but inflammation occurs when tolerance fails. How the host immune system distinguishes commensal from pathogenic signals is unclear. Our previous work shows bacteria-reactive T cells adopt distinct programs depending on the tissue niche they occupy (Gu, Nature, 2024). We hypothesise that distinct gut niches shape these T cells into divergent states, and these mechanisms support tolerance and gut health. 

  1. 10-week rotation: discover gut bacterial taxa and design a custom probe panel (Bryant Lab, Sanger). The student will apply computational methods to detect bacterial reads in human gut RNA-seq data, identifying taxa linked to inflammatory or tolerogenic responses to design a bespoke bacteria probe panel for single-cell spatial transcriptomics (VisiumHD, 10x Genomics)
  2. PhD plan: map microbe-immune interactions to gut niches and define their role in tolerance (Teichmann Lab, Cambridge). Building on the Teichmann lab's expertise in spatial genomics, the project will generate a human spatial dataset of gut microbe-immune interactions, develop analysis tools, and validate key interactions experimentally.

Aim 1: Generate a spatial dataset mapping microbe-immune interactions to gut niches

Using the custom probe panel, the student will process human gut biopsies for VisiumHD. The lab has ethical approvals and pilot VisiumHD data with commensal/pathogenic probes.

Aim 2: Develop a computational framework to analyse bacteria and immune cells in VisiumHD data. The student will build a framework mapping microbial and immune cells to spatial niches, testing whether their spatial localisation determines T-cell phenotype and function.

Aim 3: Validate bacterial signals and their spatial immune interactions. Validation will use RNAscope to detect bacteria in situ and co-cultures to confirm reactivity, alongside spatial TCR sequencing to infer TCR-MHC-antigen interaction

Principal Supervisor

Professor Sarah Teichmann

Email address: sat1003@cam.ac.uk

Department / Partner Institute: Cambridge Stem Cell Institute

Website: http://www.teichlab.org

BBSRC strategic theme

Understanding the rules of life