Daria Esterhazy

Assistant Professor
Websites
Research Summary
We study how tissue specific immunity is shaped in the digestive system under homeostatic conditions and how it can be perturbed to cause pathologies. Immunological niches in the digestive system Our goal is to understand what drives niche specific, or local, immunological differences between not only functional segments along the gut, but also the liver-biliary system and the pancreas. We postulate that this immune compartmentalization underlies the nature and site specificity of disease susceptibility, such as pathogen tropisms, food allergies, autoimmune diseases, chronic inflammatory diseases and cancers. Insight into how the immune system is wired in each niche will permit more tailored and potentially effective therapeutic strategies. Research area I: Driving forces and cellular substrates of tissue-specific lymph nodes in the digestive system Lymph nodes (LNs) are key sites for the initiation of tissue specific adaptive immunity. Along the gastrointestinal tract they are immunologically distinct (Esterhazy et al., Nature 2019), with the more proximal LNs being more tolerance-promoting and the more distal LNs more pro-inflammatory- but we wonder how extensive this paradigm is, what developmental, cellular and molecular forces underlie it, and how hardwired a LN tone is or if it can be re-established after a perturbation. Projects in the lab to address these questions include studying the active role of the gut tissue lymphatics and the lymph they carry, LN macrophages, and LN stromal cells in shaping LN niches. Research area II: Immune crosstalk between the gut, pancreas, and liver While the gut, pancreas, and liver are distinct organs, they are directly connected through shared LNs, vascular supply and ductal systems, such as the biliary and pancreatic ducts. This is due to their common developmental origin, and serves both metabolic and immunological co-ordination in response to common exposures. However, all three routes also offer unique modes of immune-modulation of one organ through more or less direct interaction with another branch of the digestive system. The extent of such reciprocal control of tissue-specific innate and adaptive immunity is our subject of investigation, with a particular focus on the impact on the pancreas and the implications for the etiology and control of pancreatic diseases such as type 1 and type 2 diabetes, pancreatitis, and pancreatic ductal adenocarcinoma. Techniques used We use a wide range of techniques in mice, including lymph node dissection, microsurgery, lymphatic vessel cannulation, pancreatic islet isolation, multimodal imaging, single cell gene expression analysis, gnotobiotics, and genetic manipulation of mice to model diseases or track immune events. We use a spectrum of gastrointestinal pathogens, and study human material to relate our work to human disease.
Keywords
Immunological niches in the digestive system, intestinal lymphatics, pancreas
Education
  • ETH Zurich, Zurich, Switzerland, PhD metabolism, pancreatic islet biology 12/2010
  • University of Cambridge, Cambridge, UK, MSci Biochemistry 06/2006
  • University of Cambridge, Cambridge, UK, BA Natural Sciences 06/2005
  • ETH Zurich, Switzerland, Postdoctoral Fellowship 2012
  • Howard Hughes Medical Institute, Postdoctoral Fellowship 2013
  • The Rockefeller University, Postdoctoral Fellowship 2018
Awards & Honors
  • 2002 - 2006 Cambridge European Trust Scholarship University of Cambridge
  • 2002 - 2006 Gonville and Caius College Scholarship University of Cambridge
  • 2012 - 2013 Early Mobility Postdoctoral fellowship Swiss National Science Foundation
  • 2012 - ETH Medal for PhD Thesis ETH Zurich
  • 2012 - Young Scientist Research Prize Swiss Diabetes Foundation
  • 2013 - 2014 Helmsley Trust Postdoctoral Fellowship The Rockefeller University
  • 2014 - 2016 Advanced Postdoctoral Fellowship Swiss National Science Foundation
Publications
  1. Wang P, Chen L, McIntosh CM, Lane JI, Li R, Xie SZ, Sattar H, Esterhazy D, Chong AS, Alegre ML. Oral alloantigen exposure promotes donor-specific tolerance in a mouse model of minor-mismatched skin transplantation. Am J Transplant. 2022 May 28. View in: PubMed

  2. Esterházy D, Canesso MCC, Mesin L, Muller PA, de Castro TBR, Lockhart A, ElJalby M, Faria AMC, Mucida D. Compartmentalized gut lymph node drainage dictates adaptive immune responses. Nature. 2019 05; 569(7754):126-130. View in: PubMed

  3. Esterházy D, Mucida D. Gut immune cells have a role in food metabolism. Nature. 2019 02; 566(7742):49-50. View in: PubMed

  4. Mucida D, Esterhazy D. SnapShot: Gut Immune Niches. Cell. 2018 09 06; 174(6):1600-1600.e1. View in: PubMed

  5. Cohen LJ, Esterhazy D, Kim SH, Lemetre C, Aguilar RR, Gordon EA, Pickard AJ, Cross JR, Emiliano AB, Han SM, Chu J, Vila-Farres X, Kaplitt J, Rogoz A, Calle PY, Hunter C, Bitok JK, Brady SF. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature. 2017 09 07; 549(7670):48-53. View in: PubMed

  6. Esterházy D, Loschko J, London M, Jove V, Oliveira TY, Mucida D. Classical dendritic cells are required for dietary antigen-mediated induction of peripheral T(reg) cells and tolerance. Nat Immunol. 2016 May; 17(5):545-55. View in: PubMed

  7. Loschko J, Schreiber HA, Rieke GJ, Esterházy D, Meredith MM, Pedicord VA, Yao KH, Caballero S, Pamer EG, Mucida D, Nussenzweig MC. Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation. J Exp Med. 2016 Apr 04; 213(4):517-34. View in: PubMed

  8. Katafuchi T, Esterházy D, Lemoff A, Ding X, Sondhi V, Kliewer SA, Mirzaei H, Mangelsdorf DJ. Detection of FGF15 in plasma by stable isotope standards and capture by anti-peptide antibodies and targeted mass spectrometry. Cell Metab. 2015 Jun 02; 21(6):898-904. View in: PubMed

  9. Brown CC, Esterhazy D, Sarde A, London M, Pullabhatla V, Osma-Garcia I, Al-Bader R, Ortiz C, Elgueta R, Arno M, de Rinaldis E, Mucida D, Lord GM, Noelle RJ. Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity. 2015 Mar 17; 42(3):499-511. View in: PubMed

  10. Lee H, Ruane D, Law K, Ho Y, Garg A, Rahman A, Esterházy D, Cheong C, Goljo E, Sikora AG, Mucida D, Chen BK, Govindraj S, Breton G, Mehandru S. Phenotype and function of nasal dendritic cells. Mucosal Immunol. 2015 Sep; 8(5):1083-98. View in: PubMed

  11. Esterházy D, Mucida D. Serum amyloid A proteins take retinol for a ride. Trends Immunol. 2014 Nov; 35(11):505-6. View in: PubMed

  12. Stützer I, Selevsek N, Esterházy D, Schmidt A, Aebersold R, Stoffel M. Systematic proteomic analysis identifies ß-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic ß-cells. J Biol Chem. 2013 Apr 12; 288(15):10536-47. View in: PubMed

  13. Vats D, Wang H, Esterhazy D, Dikaiou K, Danzer C, Honer M, Stuker F, Matile H, Migliorini C, Fischer E, Ripoll J, Keist R, Krek W, Schibli R, Stoffel M, Rudin M. Multimodal imaging of pancreatic beta cells in vivo by targeting transmembrane protein 27 (TMEM27). Diabetologia. 2012 Sep; 55(9):2407-16. View in: PubMed

  14. Esterházy D, Akpinar P, Stoffel M. Tmem27 dimerization, deglycosylation, plasma membrane depletion, and the extracellular Phe-Phe motif are negative regulators of cleavage by Bace2. Biol Chem. 2012 May; 393(6):473-84. View in: PubMed

  15. Stützer I, Esterházy D, Stoffel M. The pancreatic beta cell surface proteome. Diabetologia. 2012 Jul; 55(7):1877-89. View in: PubMed

  16. Esterházy D, Stützer I, Wang H, Rechsteiner MP, Beauchamp J, Döbeli H, Hilpert H, Matile H, Prummer M, Schmidt A, Lieske N, Boehm B, Marselli L, Bosco D, Kerr-Conte J, Aebersold R, Spinas GA, Moch H, Migliorini C, Stoffel M. Bace2 is a ß cell-enriched protease that regulates pancreatic ß cell function and mass. Cell Metab. 2011 Sep 07; 14(3):365-77. View in: PubMed

  17. Esterházy D, King MS, Yakovlev G, Hirst J. Production of reactive oxygen species by complex I (NADH:ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria. Biochemistry. 2008 Mar 25; 47(12):3964-71. View in: PubMed