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Metabolism, aging and disease

Body Barrier Immunometabolism

Body barriers allow organisms to interact with the surrounding world to sense, breath, reproduce and meet their nutritional needs. However, failure of such borders can lead to infectious diseases and cancer.

In the intestine, a healthy interplay between immune cells, epithelial cells, diet and microbes is key in preserving the intestinal epithelial barrier integrity, while also forming a front line of defence against invading pathogens.

Conventional T cells require about a week upon encounter with antigen to provide effective protection. In contrast, innate-like T cells acquire effector properties preprogrammed during development in thymus being poised for rapid and immediate response to changes at the epithelium. However, how this program is initiated is currently unclear.

The Body Barrier Immunometabolism Lab explores how innate like T cells sense dietary cues and how such signals are integrated in their development and function. In recent past, the team showed that, in addition to their developmentally regulated genetic program, immune cells are controlled by environmental cues (Nature 2014; Cell Reports 2015 and J Immunol 2016).

The team mainly focuses on unraveling the mechanisms by which micronutrients shape the development of innate-like T cells and function at mucosal barriers, such as the intestine, exploiting underlying intrinsic molecular pathways in health and disease.

We address these questions combining multi-facetted in vivo- and in vitro-based cellular and molecular technologies. These include state-of-the-art mouse genetics, flow cytometry, confocal and light sheet microscopy as well as gene expression profiling of immune and epithelial subsets.

Keywords

Early-life immune defence

Intestinal epithelium

Immune sensing

Micronutrients

Innate-like T cells

Research Lines

1 - Micronutrient Sensing and Early Life Immune Defence

We aim to elucidate how micronutrients control innate-like T cell development and function at early-life. We explore novel dietary-immune cell signaling axes relevant for the intestinal barrier function. To this end, we combine gene-reporter and tissue-specific targeting genetic mouse model strategies with highly reproducible microbial infection models (Salmonella Typhimurium and Eimeria vermiformis).

2 - Innate-like T cells and Cancer

Intestine provides absorption of nutrients, yet is exposed to massive environmental challenges and are frequently target of neoplastic transformation. Thymus-developed innate-like lymphocytes live at the intestinal mucosa, however their specific function remains poorly understood. We aim to explore the role of innate-like T cell subsets in tumour development.

3 - Mycotoxins, Early Life Immune System and Microbiota

Exposure to hazardous chemicals during early-life has been linked to an increased risk to diseases. Intestinal mucosa is the first biological barrier encountered by ingested mycotoxins and early life consequences are poorly understood. We focus on how early-life exposure to mycotoxins impacts on intestinal immune system and microbiota development.

Selected Publications

Goverse G*, Labao-Almeida C*, Ferreira M*, Molenaar R, Wahlen S, Konijn T, Koning J, Veiga-Fernandes H and Mebius ME (2016) Vitamin A controls the presence of RORγ+ innate lymphoid cells and lymphoid tissue in the small intestine. Journal of Immunology 196(12):5148-55. *Equal contribution.

(DOI: 10.4049/jimmunol.1501106)

Xu W, Domingues RG, Fonseca-Pereira D, Ferreira M, Ribeiro H, Lopez-Lastra S, Motomura Y, Moreira-Santos L, Bihl F, Braud V, Kee B, Brady H, Coles MC, Vosshenrich C, Kubo M, Di Santo JP and Veiga-Fernandes H (2015) NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Reports 10(12):2043-54.

(DOI: https://doi.org/10.1016/j.celrep.2015.02.057).

Ferreira M, Veiga-Fernandes H (2014) Pre-birth world and the development of the immune system: Mum's diet affects our adult health. Bioessays 36:1213–1220. (DOI: https://doi.org/10.1002/bies.201400115)

van de Pavert SA*, Ferreira M *, Domingues RG, Ribeiro H, Molenaar R, Moreira-Santos L, Almeida F, Ibiza S, Barbosa I, Goverse G, Labão-Almeida C, Godinho-Silva C, Konijn T, Schooneman D, O’Toole T, Mizee MR, Habani Y, Haak E, Santori FR, Littman DR, Schulte-Merker S, Dzierzak E, Simas JP, Mebius RE, Veiga-Fernandes H (2014) Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508(7494):123-7. *Equal contribution

(DOI: https://doi.org/10.1038/nature13158)

Ferreira M, Domingues RG, Veiga-Fernandes H (2012) Stroma cell priming in enteric lymphoid organ morphogenesis. Frontiers in Immunology 3:219.

(DOI: https://doi.org/10.3389/fimmu.2012.00219)

Fujiwara H, Ferreira M, Donati G, Marciano DK, Linton JM, Sato Y, Hartner A, Sekiguchi K, Reichardt LF, Watt FM (2011) The basement membrane of hair follicle stem cells is a muscle cell niche. Cell 144(4):577-89

(DOI: https://doi.org/10.1016/j.cell.2011.01.014)

Ferreira M, Fujiwara H, Morita K, Watt FM (2009) An activating beta 1 integrin mutation increases conversion of benign to malignant skin tumours. Cancer Research 69(4):1335-1342.

(DOI: 10.1158/0008-5472.CAN-08-3051)

GROUP LEADER AND PRINCIPAL INVESTIGATOR

Manuela Ferreira, PhD

ORCID

CiênciaID

Manuela Ferreira completed her PhD work at Cancer Research UK in 2010 and moved to iMM-Lisbon, and lately to Champalimaud Foundation, for postdoctoral research with H. Veiga-Fernandes. In 2020, she started setting up her laboratory at the University of Coimbra with focus on understanding how dietary cues shape innate-like lymphocytes in the healthy and diseased mucosal barriers. A main topic of research is in understanding mucosal barrier defence against pathogens at early-life and the underlying molecular and cellular pathways.

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Funded by ERDF - European Regional Development Fund through COMPETE 2020 and National Funds via FCT - Fundação para a Ciência e Tecnologia, under projects POCI-01-0145-FEDER-007440 e UIDB/04539/2020.