Targeting the p21 pathways in T cells as a new therapeutic strategy in inflammatory bowel diseases

• Applicant: Professor Maximilian Waldner, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 576091664

Inflammatory bowel disease (IBD) result in a chronic, relapsing inflammation of the digestive tract leading to severe symptoms and complications. The current pathological concept of IBD proposes that a defective epithelial barrier results in the infiltration of pathogens into the mucosal wall, which then induce a persistent activation of innate and adaptive immune cells. Among these, T cells have been regarded to be critical mediators of chronic mucosal inflammation. As a consequence, current therapies against IBD modulate the T cell response through the inhibition of pro-inflammatory cytokines, adhesion molecules, or chemotactic factors. However, not all patients respond to these therapeutics and others develop resistance during treatment. Therefore, new therapeutic options are urgently required in IBD. A newly recognized strategy to modulate pro-inflammatory effects of T cells is the induction of dysfunctional T cells states such as exhaustion or senescence. In our previous studies, we have found that defective signaling of cyclin-dependent kinase 1a (p21) in CD4+ T cells results in T cell exhaustion and reduced effector function in mouse models of colorectal cancer. In human CRC, patients with high p21 expression in CD4+ T cells showed an improved cancer-related survival compared to those with low p21 expression. Interestingly, p21 expression in CD4+ T cells is also observed in patients with IBD and is associated with the activation of pro-inflammatory pathways. On the functional level, our results show that p21-deficient mice are protected against TNBS-induced colitis compared to control animals. Furthermore, p21-deficiency was associated with a significantly reduced infiltration of memory CD4+ and CD8+ T cells into the intestine and a reduced expression of pro-inflammatory cytokines. Based on our preliminary data, we propose that p21 expression in CD4+ and CD8+ T cells plays an important role in mucosal inflammation and the inhibition of p21 signaling can induce T cell exhaustion as a therapeutic strategy in IBD patients. To address this hypothesis, we will evaluate how p21 expression is regulated in various T cell subtypes in human IBD and mice exposed to acute and chronic colitis models. Next, we will investigate the functional role of p21 in CD4+ and CD8+ T cells regarding effector/memory function, migration and metabolism to better understand how p21 signaling in T cells affects IBD initiation and progression. Finally, we will analyse, if a drug-based inhibition of p21 signaling will modulate pro-inflammatory T cell responses by inducing T cell exhaustion in preclinical colitis models in vivo and T cells isolated from human tissue samples ex vivo. Altogether, our data will help understanding the functional role of cell cycle regulatory mechanisms such as p21 in T cells in the context of mucosal inflammation, potentially providing new therapeutic strategies against IBD based on the induction of dysfunctional T cells.

• DFG Programme: Research Grants