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

Congratulations Dr. Anita Govers!

Many congratulations to Dr. Anita Govers who successfully defended her thesis "Epigenetic regulation of normal and aberrant myelopoiesis: a balancing act". It has been a long journey and super happy that we could celebrate this milestone together with co-promoter Dr. Marije Bartels. Many thanks to the thesis committee Prof. Marry van den Heuval-Eibrink, Prof. Femke van Wijk, Prof. Jurgen Kuball, Prof. Roland Kuiper, Prof. Joop Jansen en Dr. Marc Bierings.

In the last two decades, epigenetic changes have become more and more evident as a contributing factor in aberrant myelopoiesis, however the exact roles are yet poorly understood. Furthermore, knowledge about epigenetic regulation of normal hematopoiesis is far from complete. Nonetheless, the use of chromatin modifying drugs such as HDACi, has rapidly increased in the past years.

Work in this thesis is aimed to increase understanding the effects of epigenetic regulation and epigenetic modifiers on both normal and aberrant hematopoiesis.

Colorectal Cancer-Infiltrating Regulatory T Cells

Here, we review our understanding of the role of T regulatory (Treg) cells in colorectal cancer (CRC), the possible mechanisms that support their homeostasis in the tumour microenvironment, and current approaches for manipulating Treg cells function in cancer.

Colorectal cancer (CRC) is a heterogeneous disease with one of the highest rates of incidence and mortality among cancers worldwide. Understanding the CRC tumor microenvironment (TME) is essential to improve diagnosis and treatment. Within the CRC TME, tumor-infiltrating lymphocytes (TILs) consist of a heterogeneous mixture of adaptive immune cells composed of mainly anti-tumor effector T cells (CD4+ and CD8+ subpopulations), and suppressive regulatory CD4+ T (Treg) cells. The balance between these two populations is critical in anti-tumor immunity. In general, while tumor antigen-specific T cell responses are observed, tumor clearance frequently does not occur. Treg cells are considered to play an important role in tumor immune escape by hampering effective anti-tumor immune responses. Therefore, CRC-tumors with increased numbers of Treg cells have been associated with promoting tumor development, immunotherapy failure, and a poorer prognosis. Enrichment of Treg cells in CRC can have multiple causes including their differentiation, recruitment, and preferential transcriptional and metabolic adaptation to the TME. Targeting tumor-associated Treg cell may be an effective addition to current immunotherapy approaches. Strategies for depleting Treg cells, such as low dose cyclophosphamide treatment, or targeting one or more checkpoint receptors such as CTLA-4 with PD-1 with monoclonal antibodies, have been explored. These have resulted in activation of anti-tumor immune responses in CRC-patients. Overall, it seems likely that CRC-associated Treg cells play an important role in determining the success of such therapeutic approaches.

Full access to review paper here

Immunology in the Swiss mountains: WIRM meeting

The World Immune Regulation Meeting (WIRM) takes place in Davos, Switzerland. Coffer Lab PhD students Sonia Aristin and Alessandro Cutilli were both selected to present their projects in oral presentations and poster sessions. Sonia discussed her work on characterising the role of regulatory T cells in colorectal cancer. Alessandro presented his data on the effects of chemotherapy-induced damage of the intestinal epithelium on T cell homeostasis. A great offline experience with more than 400 participants. Great job guys!!





Metabolic control of lymphocyte transcription

A real pleasure to write an opinion piece for Cell Metabolism on the Vaeth Lab’s interesting study investigating novel mechanisms underlying metabolic control of transcription in lymphocytes. Here, Hochrein et al. identify a metabolic checkpoint controlling the transcriptional programming of effector CD4+ T cells. The authors show that GLUT3-mediated glucose import and ACLY-dependent acetyl-CoA generation control histone acetylation and, hence, the epigenetic imprinting of effector gene expression in differentiated effector CD4+ T cells. These findings suggest a novel therapeutic target for inflammation-associated diseases. Links to the papers are below.

Click here for Preview

Click here for Paper

Presenting @ EMBO Cancer Immunometabolism Meeting

Happy to be able to present our latest data on metabolism and autophagy in T cell activation and tolerance at the EMBO Cancer Immunometabolism meeting. https://meetings.embo.org/event/21-cancer

Tumor cells undergo metabolic changes to cope with the demands of rapid proliferation. But so do immune cells, which reprogram their metabolism when they encounter antigens and inflammatory signals. Drugs targeting cancer metabolism, as well as diets, could therefore also affect the immune system. Yet, to what extent cancer and immune cells respond in a similar fashion is currently unclear.

The immune system comprises specialized cell populations conditioned to respond rapidly to antigenic and inflammatory signals. Upon encountering antigen, the fate of CD4+ T helper cells is determined by multiple of signals they encounter which helps to shape the immune response. In addition to recognition of cognate antigen by the T cell receptor (TCR), CD4+ T cells integrate a myriad of additional cues, including signaling through costimulatory and coinhibitory receptors, interaction with other cell types, cytokines, or the type and availability of nutrients. Integration of these signals results in the induction of epigenetic and transcriptional programs driving proliferation, survival, and differentiation to T-effector cell subtypes. Changes in the activation status of CD4+ T lymphocytes not only require energy, but also increased demand for metabolic precursors for the biosynthesis of proteins, nucleic acids, and lipids. In the last decade, it has become clear that both autophagy and intracellular metabolism are essential for immune homeostasis. Productive TCR-engagement results in the induction of an unusual form of autophagy that is an absolute requirement for T cell activation. Failure to engage the autophagy machinery instead results in the induction of anergy, a hyporesponsive state. This is concomitant with a reduction in both activation-induced glycolysis and mitochondrial respiration. While it is clear that a glycolytic switch is also essential for productive T cell activation, the precise function of this remains unclear. We focus on how these processes impinge on the regulation of epigenetic and transcriptional changes required for CD4+ T cell activation and differentiation. Targeting the autophagy machinery and metabolism in the context of T cell activation may represent an effective approach to balance tolerance in immune cells.

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