Life Sciences Research for Lifelong Health

Marc Veldhoen

Marc Veldhoen is now a Group Leader at the Instituto de Medicina Molecular, Lisbon, Portugal.

His new group website is: https://imm.medicina.ulisboa.pt/en/investigacao/labs/veldhoen-marc-lab/
 

Research Summary

Epithelial barrier sites such as the skin, respiratory and gastrointestinal tract, form a physical interface between our bodies and external environments. In addition to creating a physical impediment to pathogens, epithelial barriers include a diverse mix of immune cells, forming a first line of defence against invading pathogens.

immune systemsOur laboratory studies the role that cells of the immune system play at the initiation, modulation and resolution of immune responses at epithelial barrier sites. These studies provide insights into the mechanisms that control the maintenance of a resident population of micro-organisms, promoting healthy living, and the prevention of undesirable immune responses that may result in chronic infections, allergies, autoimmunity and an increased risk of cancer.

A specialised subset of white blood cells, the intra-epithelial lymphocytes (IELs), reside just beneath the epithelial barrier of skin and intestine. They are positioned to be the first members of the immune system to interact with, and respond to, microbial populations. In addition, they help maintain a physical barrier.

Our group had demonstrated that the AhR, a receptor molecule expressed in IELs, is a crucial component for the maintenance of the IEL populations in skin and gut. This demonstrates the important roles AhR play in maintaining the physical and immunological barriers that contribute to our lifelong health and well-being.

Latest Publications

Diet-Derived Short Chain Fatty Acids Stimulate Intestinal Epithelial Cells To Induce Mucosal Tolerogenic Dendritic Cells.
Goverse G, Molenaar R, Macia L, Tan J, Erkelens MN, Konijn T, Knippenberg M, Cook EC, Hanekamp D, Veldhoen M, Hartog A, Roeselers G, Mackay CR, Mebius RE

The gastrointestinal tract is continuously exposed to many environmental factors that influence intestinal epithelial cells and the underlying mucosal immune system. In this article, we demonstrate that dietary fiber and short chain fatty acids (SCFAs) induced the expression of the vitamin A-converting enzyme RALDH1 in intestinal epithelial cells in vivo and in vitro, respectively. Furthermore, our data showed that the expression levels of RALDH1 in small intestinal epithelial cells correlated with the activity of vitamin A-converting enzymes in mesenteric lymph node dendritic cells, along with increased numbers of intestinal regulatory T cells and a higher production of luminal IgA. Moreover, we show that the consumption of dietary fiber can alter the composition of SCFA-producing microbiota and SCFA production in the small intestines. In conclusion, our data illustrate that dietary adjustments affect small intestinal epithelial cells and can be used to modulate the mucosal immune system.

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Journal of immunology (Baltimore, Md. : 1950), , 1550-6606, , 2017

PMID: 28100682

Tbet or Continued RORγt Expression Is Not Required for Th17-Associated Immunopathology.
Brucklacher-Waldert V, Ferreira C, Innocentin S, Kamdar S, Withers DR, Kullberg MC, Veldhoen M

The discovery of Th17 cell plasticity, in which CD4(+) IL-17-producing Th17 cells give rise to IL-17/IFN-γ double-producing cells and Th1-like IFNγ(+) ex-Th17 lymphocytes, has raised questions regarding which of these cell types contribute to immunopathology during inflammatory diseases. In this study, we show using Helicobacter hepaticus-induced intestinal inflammation that IL-17A(Cre)- or Rag1(Cre)-mediated deletion of Tbx21 has no effect on the generation of IL-17/IFN-γ double-producing cells, but leads to a marked absence of Th1-like IFNγ(+) ex-Th17 cells. Despite the lack of Th1-like ex-Th17 cells, the degree of H. hepaticus-triggered intestinal inflammation in mice in which Tbx21 was excised in IL-17-producing or Rag1-expressing cells is indistinguishable from that observed in control mice. In stark contrast, using experimental autoimmune encephalomyelitis, we show that IL-17A(Cre)-mediated deletion of Tbx21 prevents the conversion of Th17 cells to IL-17A/IFN-γ double-producing cells as well as Th1-like IFN-γ(+) ex-Th17 cells. However, IL-17A(Cre)-mediated deletion of Tbx21 has only limited effects on disease course in this model and is not compensated by Ag-specific Th1 cells. IL-17A(Cre)-mediated deletion of Rorc reveals that RORγt is essential for the maintenance of the Th17 cell lineage, but not immunopathology during experimental autoimmune encephalomyelitis. These results show that neither the single Th17 subset, nor its progeny, is solely responsible for immunopathology or autoimmunity.

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Journal of immunology (Baltimore, Md. : 1950), , 1550-6606, , 2016

PMID: 27183623

Effector γδ T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors.
Barros-Martins J, Schmolka N, Fontinha D, Pires de Miranda M, Simas JP, Brok I, Ferreira C, Veldhoen M, Silva-Santos B, Serre K

γδ T lymphocytes are programmed into distinct IFN-γ-producing CD27(+) (γδ27(+)) and IL-17-producing CD27(-) (γδ27(-)) subsets that play key roles in protective or pathogenic immune responses. Although the signature cytokines are shared with their αβ Th1 (for γδ27(+)) and Th17 (for γδ27(-)) cell counterparts, we dissect in this study similarities and differences in the transcriptional requirements of murine effector γδ27(+), γδ27(-)CCR6(-), and γδ27(-)CCR6(+) γδ T cell subsets and αβ T cells. We found they share dependence on the master transcription factors T-bet and RORγt for IFN-γ and IL-17 production, respectively. However, Eomes is fully dispensable for IFN-γ production by γδ T cells. Furthermore, the Th17 cell auxiliary transcription factors RORα and BATF are not required for IL-17 production by γδ27(-) cell subsets. We also show that γδ27(-) (but not γδ27(+)) cells become polyfunctional upon IL-1β plus IL-23 stimulation, cosecreting IL-17A, IL-17F, IL-22, GM-CSF, and IFN-γ. Collectively, our in vitro and in vivo data firmly establish the molecular segregation between γδ27(+) and γδ27(-) T cell subsets and provide novel insight on the nonoverlapping transcriptional networks that control the differentiation of effector γδ versus αβ T cell subsets.

+ View Abstract

Journal of immunology (Baltimore, Md. : 1950), , 1550-6606, , 2016

PMID: 26994218

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Latest Publications

Diet-Derived Short Chain Fatty Acids Stimulate Intestinal Epithelial Cells To Induce Mucosal Tolerogenic Dendritic Cells.

Goverse G, Molenaar R, Macia L

Journal of immunology (Baltimore, Md. : 1950)
1550-6606: (2017)

PMID: 28100682

Tbet or Continued RORγt Expression Is Not Required for Th17-Associated Immunopathology.

Brucklacher-Waldert V, Ferreira C, Innocentin S

Journal of immunology (Baltimore, Md. : 1950)
1550-6606: (2016)

PMID: 27183623

Effector γδ T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors.

Barros-Martins J, Schmolka N, Fontinha D

Journal of immunology (Baltimore, Md. : 1950)
1550-6606: (2016)

PMID: 26994218

Inflammation-induced formation of fat-associated lymphoid clusters.

Bénézech C, Luu NT, Walker JA

Nature immunology
1529-2916: (2015)

PMID: 26147686

Influence of nutrient-derived metabolites on lymphocyte immunity.

Veldhoen M, Ferreira C

Nature medicine
1546-170X: (2015)

PMID: 26121194

Helsinki alert of biodiversity and health.

von Hertzen L, Beutler B, Bienenstock J

Annals of medicine
1365-2060:1-8 (2015)

PMID: 25904094

Accumulation of an Endogenous Tryptophan-Derived Metabolite in Colorectal and Breast Cancers.

Puccetti P, Fallarino F, Italiano A

PloS one
10 1932-6203:e0122046 (0)

PMID: 25881064

Autophagy Controls Acquisition of Aging Features in Macrophages.

Stranks AJ, Hansen AL, Panse I

Journal of innate immunity
1662-8128: (2015)

PMID: 25764971

Feeding immunity: skepticism, delicacies and delights.

Veldhoen M, Veiga-Fernandes H

Nature immunology
16 1529-2916:215-219 (2015)

PMID: 25689432

CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection.

Linterman MA,Denton AE,Divekar DP,Zvetkova I,Kane L,Ferreira C,Veldhoen M,Clare S,Dougan G,Espeli M,Smith KG

eLife
3 2050-084X: (2014)

PMID: 25347065

Cellular Plasticity of CD4+ T Cells in the Intestine.

V Brucklacher-Waldert, EJ Carr, MA Linterman

Frontiers in immunology
5 1664-3224:488 (2014)

PMID: 25339956