PhD survivor! Congratulations to Dr. Alessandro Cutilli

On October 17th, Alessnadro defended his PhD thesis titled: CD4+ and CD8+ behaviour in the landscape of intestinal damage: Prepare for trouble and make it double. Alessandro’s work investigated how CD4+ and CD8+ T lymphocytes behave during intestinal epithelial damage. Using co-cultures of human intestinal organoids and T cells, he examined chemotherapy's affect on intestinal cells and how this subsequently impacts T cell behaviour.  Galectin-9 (Gal-9) was identified as a mediator that, when neutralized, reduces T cell proliferation and IFNγ production. Additionally he explored the effects of IFNγ-induced intestinal damage which was found to trigger the release of the chemokine CXCL11 promoting T cell migration. Finally Alessandro investigated T cell transcriptional repogramming in response to intestinal damage. These findings provide support for pre-clinical and prospective clinical investigations aimed at manipulating Gal-9 and CXCL11 to regulate T cell responses in the intestine.

You can learn more about Alessandro’s work if you click on the link here

Paper alert: How does interferon-mediated intestinal damage drive T cell recruitment?

Cytokines like interferon-gamma are key players in decisions driving inflammation and regeneration. Using a 3D co-culture model based on human intestinal organoids, PhD students Alessandro Cutilli and Suze Jansen discovered that interferon-gamma can reprogram the gut lining, leading it to express a set of pro-inflammatory genes. Specifically, they found an upregulation of chemokines CXCL9, CXCL10, and CXCL11—molecules that are key to recruiting immune cells. Their findings also showed that this reprogramming enhances T-cell migration, largely driven by CXCL11. These insights could open new therapeutic avenues: targeting CXCL11 might help prevent T-cells from trafficking to the inflamed intestine, potentially offering relief for conditions like inflammatory bowel disease (IBD). Check out the full study at:

https://pubmed.ncbi.nlm.nih.gov/39302156/

Paper alert: Chemotherapy induced intestinal damage directly modulates T cell behaviour

We have developed a human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced intestinal epithelial cell (IEC) damage on T cell behavior. This has led to the identification of galactin-9 as playing an important role in driving CD4+ and CD8+ T cell responses. Congratulations to Suze Jansen and Alessandro Cutilli for all their work driving this study forward.

Highlights

Chemotherapy-induced intestinal epithelial damage can be modelled with organoids

3D-coculture model allows evaluation of epithelial damage on T cell homeostasis

Chemotherapy-induced epithelial damage modulates T cell activation and migration

Galectin-9 promotes T cell activation and migration in response to epithelial damage

Summary

The intestine is vulnerable to chemotherapy-induced damage due to the high rate of intestinal epithelial cell (IEC) proliferation. We have developed a human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced IEC damage on T cell behavior. Exposure of intestinal organoids to busulfan, fludarabine, and clofarabine induced damage-related responses affecting both the capacity to regenerate and transcriptional reprogramming. In ex vivo co-culture assays, prior intestinal organoid damage resulted in increased T cell activation, proliferation, and migration. We identified galectin-9 (Gal-9) as a key molecule released by damaged organoids. The use of anti-Gal-9 blocking antibodies or CRISPR/Cas9-mediated Gal-9 knock-out prevented intestinal organoid damage-induced T cell proliferation, interferon-gamma release, and migration. Increased levels of Gal-9 were found early after HSCT chemotherapeutic conditioning in the plasma of patients who later developed acute GVHD. Taken together, chemotherapy-induced intestinal damage can influence T cell behavior in a Gal-9-dependent manner which may provide novel strategies for therapeutic intervention.

Chemotherapy-induced intestinal epithelial damage directly promotes galectin-9-driven modulation of T cell behavior. Suze A. Jansen# ,Alessandro Cutilli#, Coco de Koning, Marliek van Hoesel,Cynthia L. Frederiks, Leire Saiz Sierra,Stefan Nierkens, Michal Mokry, Edward E.S. Nieuwenhuis,Alan M. Hanash, Enric Mocholi, Paul J. Coffer* and Caroline A. Lindemans*

Welcome Claudia!

Cláudia Leite graduated in Biochemistry and holds a PhD in Molecular and Cell Biology from the University of Porto. During her PhD, she investigated how mitochondria adjusts their activity to regulate cell cycle progression in budding yeast. She has recently joined the Coffer lab as a postdoctoral researcher to investigate the role of nuclear acetyl-CoA-producing enzymes in regulating transcriptional reprograming.

Lab day out: canoeing in Holland's beautiful 'green heart'

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Paper: Nuclear metabolism controls chromatin remodelling during T cell activation

Extremely happy to have our study exploring nuclear metabolism in the control of chromatin remodeling published (link below). This became a huge project driven by Enric Mocholi and wouldn't have been possible without generous collaborations from groups in the EU, USA and Canada (through lockdown). A BIG thank you to all involved.

In brief

After T cell activation, histone acetylation and transcriptional reprogramming require glycolysis and the pyruvate dehydrogenase (PDH)-dependent production of extramitochondrial acetyl-CoA. Here we show that PDH translocates to the nucleus close to chromatin-remodeling complexes, highlighting how metabolic and histone-modifying enzymes cooperate in regulating T cell activation.

Highlights

- PDH is required for histone acetylation and transcription after T cell activation

- MPC1 and ACLY are not required for T cell activation and transcriptional reprogramming

- T cell activation leads to PDH nuclear translocation close to chromatin-remodeling complexes

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