TIGIT+CD38+ effector cells: New players in suppressing inflammation in IBD?
|Janneke N. Samsom
© Janneke N. Samsom
Background and Hypothesis
In Inflammatory Bowel Disease (IBD), T-cell reactivity against harmless microbial antigens drives chronic inflammation. After induction of remission, patients receive T-cell-suppressing maintenance treatment, which is effective in maintaining remission in some patients but not others. “T-cell immunoglobulin and ITIM domain” (TIGIT) is a novel inhibitor of T-cell activation. Preliminary experiments show that human circulating TIGIT-expressing CD38+ effector T cells are concomitantly enriched in the inhibitory molecules IL-10, PD-1 and CTLA-4. Crucially, frequencies of these cells were much reduced in a subgroup of paediatric IBD patients at disease onset and associated with reduced duration of clinical remission during follow-up.
We hypothesise that TIGIT+CD38+ effector T cells are functionally involved in immune regulation of microbial responses in the gastrointestinal tract.
Aims and Methodology
In this project we aim to:
- Establish that TIGIT expression in CD38+ effector T cells plays a role in maintaining tolerance to harmless intestinal microbiota. Intestinal morphology and immune responses in TIGIT-deficient mice will be studied at steady state and after induction of experimental colitis (year 1 and year 2). In vitro cultures will assess mechanisms by which TIGIT regulates mucosal T-cell function in mouse and human.
- Determine the factors that drive TIGIT expression in CD38+ effector T cells (year 1). Murine germ-free mouse colonisation studies in combination with human and mouse cell cultures will establish the signals driving TIGIT expression.
- Relate the frequencies of TIGIT+ expressing CD38+ effector T cells to disease activity, disease course and therapy responsiveness. In our cohort of longitudinally followed paediatric IBD patients we will compare disease course and therapy responsiveness in patients with low and high frequencies of TIGIT+CD38+ effector T cells and relate these frequencies to currently available biomarkers (year 1 and year 2).
Overall, this project will reveal the value of monitoring TIGIT+CD38+ effector T cells for the development of future tailored IBD therapy.