Marc Veldhoen Lab

Regulação do Sistema Imunitário

Os tecidos epiteliais como a pele, o sistema respiratório e o sistema gastrointestinal funcionam como uma barreira entre o nosso organismo e os fatores externos. Estes tecidos para além de formarem uma barreira física que impede a passagem de agentes invasores, também incluem diversas células do sistema imunitário, que constituem a primeira linha de defesa contra microorganismos patogénicos.

A investigação que desenvolvemos pretende estudar a função das células do sistema imunitário na iniciação, modulação e resolução da resposta imune nos tecidos epiteliais, bem como na regulação da homeostase das células epiteliais. Este estudo pretende esclarecer os mecanismos que controlam a manutenção, ativação e função das células do sistema imunitário localizadas nas mucosas ou que se acumulam nestes tecidos. Deste modo, o objetivo do nosso laboratório é contribuir para a prevenção de respostas imunes indesejadas que podem resultar em infecções crónicas, alergias, doenças auto-imunes e risco aumentado de cancro.

Marc Veldhoen | Era Chair Holder - This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667824.

Equipa de Investigação

Áreas de Investigação

• Interações entre células imunes e células epiteliais
• Homeostase tecidular
• Diferenciação de células T helper
• Influência dos fatores ambientais na imunidade
• Imunologia das mucosas

Projetos de Investigação em Curso

2019/2022 Enhancing Tissue Resident Immunity. Coordenação: Marc Veldhoen. Agência Financiadora: "la Caixa" Foundation.

2018/2021 Regulação da rede de resposta imunológica epitelial. Coordenação: Marc Veldhoen. Agência Financiadora: Fundação para a Ciência e a Tecnologia.

2015/2020 EXCELLtoINNOV: Leverage research EXCELLence and INNOVation potential of Instituto de Medicina Molecular (iMM) trough translational biomedical research in Immunity and Infection. Coordenação: Marc Veldhoen. Agência Financiadora: Comissão Europeia.

Prémios

2011 EMBO Young Investigator programme

2010 ERC starting grant

Publicações Selecionadas

Stark AK, Davenport ECM, Patton DT, Scudamore CL, Vanhaesebroeck B, Veldhoen M, Garden OA, Okkenhaug K (2020). Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation. Journal of Immunology. doi: 10.4049/jimmunol.2000043.

Ferreira C, Barros L, Baptista M, Blankenhaus B, Barros A, Figueiredo-Campos P, Konjar Š, Lainé A, Kamenjarin N, Stojanovic A, Cerwenka A, Probst HC, Marie JC, Veldhoen M (2020). Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cells. Nature Immunology. doi: 10.1038/s41590-020-0674-9.

Kazakevych J, Denizot J, Liebert A, Portovedo M, Mosavie M, Jain P, Stellato C, Fraser C, Corrêa RO, Célestine M, Mattiuz R, Okkenhaug H, Miller JR, Vinolo MAR, Veldhoen M, Varga-Weisz P (2020). Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium. Genome Biology. doi: 10.1186/s13059-020-01976-7.

Cossarizza A, Chang HD, Radbruch A, Acs A, Adam A, Adam‐Klages S, Agace W et al. (2019). Guidelines for the use of flow cytometry and cell sorting in immunological studies. European Journal of Immunology. doi: 10.1002/eji.201970107.

Ariotti S, Veldhoen M (2019). Immunology: Skin T Cells Switch Identity to Protect and Heal. Current Biology. doi: 10.1016/j.cub.2019.01.055.

Singh Y, Zhang S, Al-Maghout T, Cao I, Pelzl L, Salker M, Veldhoen M, Cheng A, Lang F (2019). Gut bacterial metabolite Urolithin A (UA) mitigates Ca2+ entry in T cells by regulating miR-10a-5p. Frontiers in Immunology. doi: 10.3389/fimmu.2019.01737.

Konjar S, Veldhoen M (2019). Dynamic metabolic state of tissue resident CD8 T cells. Frontiers in Immunology. doi: 10.3389/fimmu.2019.01683

Figueiredo-Campos P, Ferreira C, Blankenhaus B, Veldhoen M (2018). Eimeria vermiformis Infection Model of Murine Small Intestine. Bio-Protocols. 10.21769/BioProtoc.3122.

Veldhoen M, Blankenhaus B, Konjar Š, Ferreira C (2018). Metabolic wiring of murine T cell and intraepithelial lymphocyte maintenance and activation. European Journal of Immunology. doi: 10.1002/eji.201646745.

Konjar Š, Frising UC, Ferreira C, Hinterleitner R, Mayassi T, Zhang Q, Blankenhaus B, Haberman N, Loo Y, Guedes J, Baptista M, Innocentin S, Stange J, Strathdee D, Jabri B, Veldhoen M (2018). Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes. Science Immunology. doi: 10.1126/sciimmunol.aan2543.

Fellows R, Denizot J, Stellato C, Cuomo A, Jain P, Stoyanova E, Balázsi S, Hajnády Z, Liebert A, Kazakevych J, Blackburn H, Corrêa RO, Fachi JL, Sato FT, Ribeiro WR, Ferreira CM, Perée H, Spagnuolo M, Mattiuz R, Matolcsi C, Guedes J, Clark J, Veldhoen M, Bonaldi T, Vinolo MAR, Varga-Weisz P (2018). Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nature Communications. doi: 10.1038/s41467-017-02651-5.

Š. Konjar, B. Blankenhaus, M. Veldhoen (2018). Oxygen starvation during T cell priming boosts cancer-killing potential. Translational Cancer Research.

Brucklacher-Waldert V, Ferreira C, Stebegg M, Fesneau O, Innocentin S, Marie JC, Veldhoen M (2017). Cellular Stress in the Context of an Inflammatory Environment Supports TGF-β-Independent T Helper-17 Differentiation. Cell Rep.

Veldhoen M (2017). Interleukin 17 is a chief orchestrator of immunity. Nature Immunology.

Stubbs TM, Bonder MJ, Stark AK, Krueger F; BI Ageing Clock Team, von Meyenn F, Stegle O, Reik W (2017). Multi-tissue DNA methylation age predictor in mouse. Genome Biology.

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 (2017). Diet-Derived Short Chain Fatty Acids Stimulate Intestinal Epithelial Cells To Induce Mucosal Tolerogenic Dendritic Cells. The Journal Immunology.

Veldhoen M (2017). Th17 Cells Require You to Chew before You Swallow. Immunity.

Konjar Š, Ferreira C, Blankenhaus B, Veldhoen M (2017). Intestinal Barrier Interactions with Specialized CD8 T Cells. Frontiers in Immunology.

Cossarizza, A., Chang, H.-D., Radbruch, A., Andrä, I., Annunziato, F., Bacher, P., Barnaba, V., Battistini, L., Bauer, W. M., Baumgart, S., Becher, B., Beisker, W., Berek, C., Blanco, A., Borsellino, G., Boulais, P. E., Brinkman, R. R., Büscher, M., Busch, D. H., Bushnell, T. P., Cao, X., Cavani, A., Chattopadhyay, P. K., Cheng, Q., Chow, S., Clerici, M., Cooke, A., Cosma, A., Cosmi, L., Cumano, A., Dang, V. D., Davies, D., De Biasi, S., Del Zotto, G., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Diefenbach, A., Di Santo, J., Dieli, F., Dolf, A., Donnenberg, V. S., Dörner, T., Ehrhardt, G. R. A., Endl, E., Engel, P., Engelhardt, B., Esser, C., Everts, B., Falk, C. S., Fehniger, T. A., Filby, A., Fillatreau, S., Follo, M., Förster, I., Foster, J., Foulds, G. A., Frenette, P. S., Galbraith, D., Garbi, N., García-Godoy, M. D., Ghoreschi, K., Gibellini, L., Goettlinger, C., Goodyear, C. S., Gori, A., Grogan, J., Gross, M., Grützkau, A., Grummitt, D., Hahn, J., Hammer, Q., Hauser, A. E., Haviland, D. L., Hedley, D., Herrera, G., Herrmann, M., Hiepe, F., Holland, T., Hombrink, P., Houston, J. P., Hoyer, B. F., Huang, B., Hunter, C. A., Iannone, A., Jäck, H.-M., Jávega, B., Jonjic, S., Juelke, K., Jung, S., Kaiser, T., Kalina, T., Keller, B., Khan, S., Kienhöfer, D., Kroneis, T., Kunkel, D., Kurts, C., Kvistborg, P., Lannigan, J., Lantz, O., Larbi, A., LeibundGut-Landmann, S., Leipold, M. D., Levings, M. K., Litwin, V., Liu, Y., Lohoff, M., Lombardi, G., Lopez, L., Lovett-Racke, A., Lubberts, E., Ludewig, B., Lugli, E., Maecker, H. T., Martrus, G., Matarese, G., Maueröder, C., McGrath, M., McInnes, I., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Mills, K., Mjösberg, J., Moore, J., Moran, B., Moretta, A., Moretta, L., Mosmann, T. R., Müller, S., Müller, W., Münz, C., Multhoff, G., Munoz, L. E., Murphy, K. M., Nakayama, T., Nasi, M., Neudörfl, C., Nolan, J., Nourshargh, S., O'Connor, J.-E., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Peterson, P., Peth, C., Petriz, J., Philips, D., Pickl, W., Piconese, S., Pinti, M., Pockley, A. G., Podolska, M. J., Pucillo, C., Quataert, S. A., Radstake, T. R. D. J., Rajwa, B., Rebhahn, J. A., Recktenwald, D., Remmerswaal, E. B.M., Rezvani, K., Rico, L. G., Robinson, J. P., Romagnani, C., Rubartelli, A., Ruland, J., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sawitzki, B., Scheffold, A., Schiemann, M., Schildberg, F., Schimisky, E., Schmid, S. A., Schmitt, S., Schober, K., Schüler, T., Schulz, A. R., Schumacher, T., Scotta, C., Shankey, T. V., Shemer, A., Simon, A.-K., Spidlen, J., Stall, A. M., Stark, R., Stehle, C., Stein, M., Steinmetz, T., Stockinger, H., Takahama, Y., Tarnok, A., Tian, Z., Toldi, G., Tornack, J., Traggiai, E., Trotter, J., Ulrich, H., van der Braber, M., van Lier, R. A. W., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H.-D., von Volkmann, K., Waisman, A., Walker, R., Ward, M. D., Warnatz, K., Warth, S., Watson, J. V., Watzl, C., Wegener, L., Wiedemann, A., Wienands, J., Willimsky, G., Wing, J., Wurst, P., Yu, L., Yue, A., Zhang, Q., Zhao, Y., Ziegler, S. and Zimmermann, J. (2017), Guidelines for the use of flow cytometry and cell sorting in immunological studies. European Journal of Immunology.

Brucklacher-Waldert, V., Ferreira, C., Innocentin, S., Kamdar, S., Withers, D.R., Kullberg, C.M., and Veldhoen, M. (2016). Tbet or continued RORγt expression are not required for Th17-associated immunopathology. Journal of Immunology.

Barros-Martins, J., Schmolka, N., Fontinha, D., Pires de Miranda, M., Simas, J.P., Brok, I., Ferreira, C., Veldhoen, M., Silva-Santos, B., and Serre, K. (2016). Effector gammadelta T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors. Journal of Immunology.

Withers, D.R., Hepworth, M.R., Wang, X., Mackley, E.C., Halford, E.E., Dutton, E.E., Marriott, C.L., Brucklacher-Waldert, V., Veldhoen, M., Kelsen, J., et al. (2016). Transient inhibition of ROR-gammat therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nature Medicine 22, 319-323.

Bénézech, C., N-T. Luu, J.A. Walker, A.A Kruglov, Y. Loo, K. Nakamura, Y. Zhang, S. Nayar, L.H. Jones, A. Flores-Lanarica, A. McIntosh, J. Marshall, F. Barone, G. Besra, K. Miles, J.E. Allen, M. Gray, G. Kollias, A.F. Cunningham, D. Withers, K.M. Toellner, N.D. Jones, M. Veldhoen, S.A. Nedospasov, A.N.J. McKenzie and J.H. Caamaño. (2015) Inflammation-Induced Formation of Fat-Associated Lymphoid Clusters. Nature Immunology 16, 819-828.

Puccetti, P. , F. Fallarino, A. Italiano, I. Soubeyran, G. MacGrogan, M. Debled, V. Velasco, D. Bodet, S. Eimer, M. Veldhoen, G.C. Prendergast, M. Platten, A. Bessede and G. Guillemin. (2015) Accumulation of an Endogenous Tryptophan-Derived Metabolite in Colorectal and Breast Cancers. PLoS One 10, e0122046.

Stranks, A. J., A. L. Hansen, I. Panse, M. Mortensen, D. J. Ferguson, D. J. Puleston, K. Shenderov, A. S. Watson, M. Veldhoen, K. Phadwal, V. Cerundolo and A. K. Simon. (2015) Autophagy Controls Acquisition of Aging Features in Macrophages. Journal of Innate Immunology 7, no. 4 (2015): 375-391.

Linterman, M.A., Denton, A.E., Divekar, D.P., Zvetkova, I., Kane, L., Ferreira, C., Veldhoen, M., Clare, S., Dougan, G., Espeli, M., et al. (2014). CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection. eLife 3.

Marriott, C.L., Mackley, E.C., Ferreira, C., Veldhoen, M., Yagita, H., and Withers, D.R. (2014). OX40 controls effector CD4(+) T-cell expansion, not follicular T helper cell generation in acute Listeria infection. European Journal of Immunology 44, 2437-2447.

Zaid, A., Mackay, L.K., Rahimpour, A., Braun, A., Veldhoen, M., Carbone, F.R., Manton, J.H., Heath, W.R., and Mueller, S.N. (2014). Persistence of skin-resident memory T cells within an epidermal niche. Proceedings of the National Academy of Sciences of the United States of America 111, 5307-5312.

Sriskantharajah, S., Guckel, E., Tsakiri, N., Kierdorf, K., Brender, C., Ben-Addi, A., Veldhoen, M., Tsichlis, P.N., Stockinger, B., O'Garra, A., et al. (2014). Regulation of experimental autoimmune encephalomyelitis by TPL-2 kinase. Journal of Immunology 192, 3518-3529.

Mastelic, B., Freitas do Rosario, A.P., Veldhoen, M., Renauld, J.-C., Jarra, W., Sponaas, A.-M., Roetynck, S., Stockinger, B., and Langhorne, J. (2012). IL-22 protects against liver pathology and lethality of an experimental blood-stage malaria infection. Frontiers in Immunology 3.

Li, Y., Innocentin, S., Withers, D.R., Roberts, N.A., Gallagher, A.R., Grigorieva, E.F., Wilhelm, C., and Veldhoen, M. (2011). Exogenous Stimuli Maintain Intraepithelial Lymphocytes via Aryl Hydrocarbon Receptor Activation. Cell 147, 629-640.

Hirota, K., Duarte, J.H., Veldhoen, M., Hornsby, E., Li, Y., Cua, D.J., Ahlfors, H., Wilhelm, C., Tolaini, M., Menzel, U., et al. (2011). Fate mapping of IL-17-producing T cells in inflammatory responses. Nature Immunology 12, 255-263.

Teixeira-Coelho, M., Cruz, A., Carmona, J., Sousa, C., Ramos-Pereira, D., Saraiva, A.L., Veldhoen, M., Pedrosa, J., Castro, A.G., and Saraiva, M. (2011). TLR2 deficiency by compromising p19 (IL-23) expression limits Th 17 cell responses to Mycobacterium tuberculosis. International Immunology 23, 89-96

Martin, B., Hirota, K., Cua, D.J., Stockinger, B., and Veldhoen, M. (2009). Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321-330.

Saraiva, M., Christensen, J.R., Veldhoen, M., Murphy, T.L., Murphy, K.M., and O'Garra, A. (2009). Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31, 209-219.

Bending, D., De La Pena, H., Veldhoen, M., Phillips, J.M., Uyttenhove, C., Stockinger, B., and Cooke, A. (2009). Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 119, 565–572.

Veldhoen, M., Hirota, K., Christensen, J., O'Garra, A., and Stockinger, B. (2009). Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. The Journal of Experimental Medicine 206, 43-49.

Veldhoen, M., Uyttenhove, C., van Snick, J., Helmby, H., Westendorf, A., Buer, J., Martin, B., Wilhelm, C., and Stockinger, B. (2008). Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immunology 9, 1341-1346.

Veldhoen, M., Hirota, K., Westendorf, A.M., Buer, J., Dumoutier, L., Renauld, J.C., and Stockinger, B. (2008). The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106-109.

Veldhoen, M., Hocking, R.J., Flavell, R.A., and Stockinger, B. (2006). Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nature Immunology 7, 1151-1156.

Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M., and Stockinger, B. (2006). TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179-189.

Veldhoen, M., Moncrieffe, H., Hocking, R.J., Atkins, C.J., and Stockinger, B. (2006). Modulation of dendritic cell function by naive and regulatory CD4+ T cells. J Immunol 176, 6202-6210.

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