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Marc Veldhoen Lab

Immune regulation

Our laboratory studies how T lymphocytes develop, are maintained, activated and differentiate to acquire particular functional properties. We are interested in the role that T cells play at the initiation, modulation and resolution of immune responses in tissues. In addition, we study the detailed molecular events that modulate T cells, especially signaling pathways and metabolic requirements that determine their development, activation and differentiation. These studies provide insights into the mechanisms that control the maintenance, activation and function of immune cells located or enriched in organs, ultimately contributing to the prevention of undesirable immune responses that may result in chronic infections, allergies, autoimmunity and an increased risk of cancer.

Our lab is interested in all areas of T cell biology. We have made seminal contribution by discovering the differentiation of Thelper-17 and Thelper-9 cells, and a role for the arylhydrocarbon receptor in T cells, including in innate-like T cells. This has led us into two main areas of current focus: the role of tissue resident memory T (Trm) cells in infection and in tumour therapy, and the interactions between molecular and metabolic pathways in T cell biology.

1) Despite advances in early diagnosis and treatment, cancer remains a huge challenge, requiring innovative therapeutic approaches. Traditional therapies, such as chemotherapy and radiotherapy, have significant unwanted side effects, making new, more targeted and less toxic approaches highly necessary. In the case of blood cancers, significant advances have been made with CAR-T cell therapies and immune checkpoint inhibitors. However, the success of these treatments in solid tumours remains limited. In this context, the lab focuses on a type of immune system cell, the tissue resident memory T lymphocytes, which are able to penetrate tissues and eliminate cancerous or infected cells, and which could hold the key to improving cancer therapies by making them more targeted and effective. We have developed and patented an in vitro protocol for the production of these memory T cells and their therapeutic application as an immunotherapy against cancer. We are interested in the biology of Trm cells, their function and their maintenance in tissues.

2) Infectious and inflammatory diseases, whose prevalence is increasing globally, are one of the leading causes of mortality worldwide. Many of these pathologies are related to the activity of T-lymphocytes, a type of white blood cell responsible for orchestrating the immune attack against pathogens. Sometimes, these defensive cells overreact, which can lead to the development of serious conditions such as fibrosis, chronic obstructive pulmonary disease or asthma. To avoid these complications, broad-spectrum immunosuppressive drugs are often administered; however, they have significant side effects and increase the risk of infection. This makes it necessary to develop new therapeutic options that can selectively inhibit the activity of T-lymphocytes.

Our lab discovered that T cells possess a previously unidentified pathway that is important for their activation and may link this with the metabolic capacity of T cells. In the current projects, we aim to map several factors associated with this pathway and validate their role in T cell biology as well as investigating these factors as a potential new therapeutic targets. In collaborative efforts, we try to identify drugs that can modulate the T lymphocyte response without affecting the rest of the protective immune function.

1) The role of tissue resident memory T (Trm) cells in infection and tumour therapy

2) The role of signaling components connecting T cell development, activation and maintenance with their metabolic capacity

L. Barros, D. Piontkivska, P. Figueiredo-Campos, et al. (2023). CD8+ tissue-resident memory T-cell development depends on infection-matching regulatory T-cell types. Nature Communications 14: 5579. https://doi.org/10.1038/s41467-023-41364-w.

Š. Konjar, C. Ferreira, F.S. Carvalho, P. Figueiredo-Campos, J. Fanczal, S. Ribeiro, V.A. Morais, M. Veldhoen (2022). Intestinal tissue-resident T-cell activation depends on metabolite availability. Proceedings of the National Academy of Sciences, USA 119(34): e2202144119. https://doi.org/10.1073/pnas.2202144119.

C. Ferreira, L. Barros, M. Baptista, et al. (2020). Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cells. Nature Immunology 21: 766–776. https://doi.org/10.1038/s41590-020-0674-9.

Š. Konjar, et al. (2018). Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes. Science Immunology 3: eaan2543. https://doi.org/10.1126/sciimmunol.aan2543.

V. Brucklacher-Waldert*, C. Ferreira*, M. Stebegg, et al. (2017). Cellular stress in the context of an inflammatory environment supports TGF-β-independent T Helper-17 differentiation. Cell Reports 19(11): 2357–2370. co-first authors.

Y. Li, S. Innocentin, D.R. Withers, et al. (2011). Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147(3): 629–640. https://doi.org/10.1016/j.cell.2011.09.025.

M. Veldhoen, C. Uyttenhove, J. van Snick, et al. (2008). Transforming growth factor-β ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset. Nature Immunology 9: 1341–1346. https://doi.org/10.1038/ni.1659.

M. Veldhoen, K. Hirota, A. Westendorf, et al. (2008). The aryl hydrocarbon receptor links Th17-cell-mediated autoimmunity to environmental toxins. Nature 453: 106–109. https://doi.org/10.1038/nature06881.

M. Veldhoen, R. Hocking, R. Flavell, et al. (2006). Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nature Immunology 7: 1151–1156. https://doi.org/10.1038/ni1391.

M. Veldhoen, R.J. Hocking, C.J. Atkins, R.M. Locksley, B. Stockinger (2006). TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2): 179–189. https://doi.org/10.1016/j.immuni.2006.01.001.

EMBO young investigator 2010

ERC consolidator grant 2010

“la Caixa” Foundation HealthResearch award 2019, 2023