The gastrointestinal tract is one of the major sites of immunological challenge to the host immune system. Here the host must be able to mount protective immune responses against invading pathogenic micro-organisms while, at the same time specifically not activating these mechanisms in response to dietary antigens or the beneficial normal enteric flora. In the intestine, therefore, perhaps more than any other organ, immune reactivity must be tightly regulated to ensure induction of protective and not pathologic responses.

The research interests of the group include dissection of the factors that control the mutualistic relationship between commensal bacteria and the intestinal immune system and how this breaks down in inflammatory bowel disease. We have a particular interest in T cell: DC interactions and cytokine networks in the intestine and how these influence the balance between effector and regulatory T cells responses. We combine model systems of intestinal inflammation and colon cancer with the study of innate and adaptive immune responses in inflammatory bowel disease (IBD) patients.

Projects in Lab

Identification of innate and adaptive pathways of intestinal inflammation

Utilizing models of colitis we have shown that intestinal inflammation is a consequence of a chronic immune response triggered by enteric bacteria. Both innate and adaptive immune mechanisms can cause colitis with elevations of the pro-inflammatory cytokines, IL-6, IFN-g, IL-12/IL-23p40 and TNF-a. Recently, we have re-evaluated the role of IL-12 in orchestrating intestinal inflammation. Strikingly, our new data show that IL-23 and not IL-12 drives intestinal immune pathology. This has also been established for T cell independent innate immune pathology providing the first evidence that IL-23 plays a key role in the innate immune response independent of its effects on T cells. By contrast with the local immune response, systemic immune activation accompanying T cell-independent colitis was functionally dependent on IL-12 but not IL-23. The differential role of IL-23 in local but not systemic inflammation suggests it may make a more specific target for the treatment of chronic inflammation. Human genome wide association studies have identified common variants of the IL23R gene that confer risk in IBD. Our current research seeks to further understand IL23R mediated innate and adaptive immune pathways in intestinal inflammation and repair. We have collaborative studies with John O'Shea at the NIH to identify STAT-3 targets that are linked to chronic intestinal inflammation.

Genetic susceptibility alleles in colon cancer

Patients with IBD are at increased risk of developing colon cancer but little is known about the cellular and molecular pathways Adenocarcinoma picture that drive tumourigenesis in the intestine. Using a model of inflammation -driven bacteria-induced colon cancer we are performing genetic mapping studies to identify genes that influence the development of colon cancer. We are also studying these pathways in colon cancer patients. This work is part of the EU-funded FP7 Programme INFACARE that brings together a number of European labs working on cellular and molecular pathways in inflammation-driven cancer

Dendritic cell subsets and intestinal immunity

Drentic picture Dendritic cells are abundant in the intestine and represent a heterogeneous population of cells that mediate diverse immune functions. In recent work we have identified a distinct subset of DC that express the alpha e integrin and are present at high frequency in the intestine. Under homeostatic conditions CD103+ DC promote regulatory T cell responses via a TGF-beta and retinoic acid dependent mechanism. Current work involves understanding the factors in the intestine that condition DC function and how this changes in inflammation.

Regulatory T cells

Our studies have also shown that functionally specialized populations of regulatory T cells (Treg) play an important role in T cells maintaining intestinal homeostasis. Thus, naturally arising CD4⁺CD45RB^lowCD25⁺prevent and most importantly cure intestinal inflammation induced by both adaptive and innate immune responses. These results suggest that stimulation of Treg responses may be beneficial for the treatment of IBD. In response to inflammation Treg cells proliferate in the secondary lymphoid tissue and locally in the intestine suggesting they may act at both sites to curtail the inflammatory response. Mechanistic analysis of Treg-mediated control of colitis showed functional roles for both IL-10 and TGF-b. Expression of CTLA4 on Treg cells themselves also plays an important role. Significantly, like the effector response that drives intestinal inflammation there is also compartmentalization of the Treg response as IL-10 secreting Treg cells are contained at higher frequency in the intestine compared to secondary lymphoid tissue. In addition we have recently shown that the intestine is a site for the development of Foxp3+ Treg cells from naïve precursors and that these cells also contribute to intestinal homeostasis. Our current work focuses on the role of costimulatory pathways in Treg homeostasis in the gut and the specificity and function of distinct Treg subsets in the gut. An understanding of how the body naturally prevents development of inflammatory responses in the intestine may provide important information for the design of immune therapies efficacious for the treatment of a number of autoimmune and inflammatory diseases.

We work closely with Dr Kevin Maloy's lab who works on host-pathogen interactions and innate immune regulation in the intestine: Projects in collaboration with Kevin Maloy (Lab Website)

Group Members

Natasha Fewkes

Scott Steward-Tharp

Group Publications

1. Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L, Takahashi H, Sun HW, Kanno Y, Powrie F, O'Shea JJ. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010;32(5):605-15. [Pubmed]

2. Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, Powrie F. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 2010;464(7293):1371-5. [Pubmed]

3. Laffont S, Siddiqui KR, Powrie F. Intestinal inflammation abrogates the tolerogenic properties of mln cd103(+) dendritic cells. Eur J Immunol. 2010;40(7):1877-83. [Pubmed]

4. Asquith MJ, Boulard O, Powrie F, Maloy KJ. Pathogenic and protective roles of MyD88 in leukocytes and epithelial cells in mouse models of inflammatory bowel disease. Gastroenterology. 2010. [Pubmed]

5. Siddiqui KR, Laffont S, Powrie F. E-cadherin marks a subset of inflammatory dendritic cells that promote T cell-mediated colitis. Immunity. 2010;32(4):557-67. [Pubmed]

6. Griseri T, Asquith M, Thompson C, Powrie F. OX40 is required for regulatory T cell-mediated control of colitis. J Exp Med. 2010;207(4):699-709. [Pubmed]

7. Boulard O, Asquith MJ, Powrie F, Maloy KJ. TLR2-independent induction and regulation of chronic intestinal inflammation. Eur J Immunol. 2010;40(2):516-24. [Pubmed]

8. Laffont S, Powrie F. Immunology: Dendritic-cell genealogy. Nature. 2009;462(7274):732-3. [Pubmed]

9. Barnes MJ, Powrie F. Regulatory T cells reinforce intestinal homeostasis. Immunity. 2009;31(3):401-11. [Pubmed]

10. Uhlig HH, Powrie F. Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease. Eur J Immunol. 2009;39(8):2021-6. [Pubmed]

11. Barnes MJ, Powrie F. Hybrid Treg cells: steel frames and plastic exteriors. Nat Immunol. 2009;10(6):563-4. [Pubmed]

12. Izcue A, Coombes JL, Powrie F. Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol. 2009;27:313-38. [Pubmed]

13. Ahern PP, Izcue A, Maloy KJ, Powrie F. The interleukin-23 axis in intestinal inflammation. Immunol Rev. 2008;226:147-59. [Pubmed]

14. Toms C, Jessup H, Thompson C, Baban D, Davies K, Powrie F. Gpr83 expression is not required for the maintenance of intestinal immune homeostasis and regulation of T-cell-dependent colitis. Immunology. 2008;125(3):302-12. [Pubmed]

15. Siddiqui KR, Powrie F. CD103+ GALT DCs promote Foxp3+ regulatory T cells. Mucosal Immunol. 2008;1 Suppl 1:S34-8. [Pubmed]

16. Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL, Berg PL, Davidsson T, Powrie F, Johansson-Lindbom B, Agace WW. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. J Exp Med. 2008; 205(9):2139-49. [Pubmed]

17. Coombes JL, Powrie F. Dendritic cells in intestinal immune regulation. Nat Rev Immunol. 2008; 8(6):435-46. [Pubmed]

18. Izcue A, Hue S, Buonocore S, Arancibia-Cárcamo CV, Ahern PP, Iwakura Y, Maloy KJ, Powrie F. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity. 2008; 28(4):559-70. [Pubmed]

19. Izcue A, Powrie F. Special regulatory T-cell review: Regulatory T cells and the intestinal tract--patrolling the frontier. Immunology. 2008; 123(1):6-10. [Pubmed]

20. Willoughby JE, Costello PS, Nicolas RH, Robinson NJ, Stamp G, Powrie F, Treisman R. Raf signaling but not the ERK effector SAP-1 is required for regulatory T cell development. J Immunol. 2007; 179(10):6836-44. [Pubmed]

21. McGovern D, Powrie F. The IL23 axis plays a key role in the pathogenesis of IBD. Gut. 2007; 56(10):1333-6. [Pubmed]

22. Stepankova R, Powrie F, Kofronova O, Kozakova H, Hudcovic T, Hrncir T, Uhlig H, Read S, Rehakova Z, Benada O, Heczko P, Strus M, Bland P, Tlaskalova-Hogenova H. Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells. Inflamm Bowel Dis. 2007; 13(10):1202-11. [Pubmed]

23. Coombes JL, Siddiqui KR, Arancibia-Cárcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007; 204(8):1757-64. [Pubmed]

24. Sakaguchi S, Powrie F. Emerging challenges in regulatory T cell function and biology. Science. 2007; 317(5838):627-9. [Pubmed]

25. Banham AH, Powrie FM, Suri-Payer E. FOXP3+ regulatory T cells: Current controversies and future perspectives. Eur J Immunol. 2006; 36(11):2832-6. [Pubmed]

26. Cousins L, Graham M, Tooze R, Carter C, Miller JR, Powrie FM, Macpherson GG, Butcher GW. Eosinophilic bowel disease controlled by the BB rat-derived lymphopenia/Gimap5 gene. Gastroenterology. 2006; 131(5):1475-85. [Pubmed]

27. Uhlig HH, Coombes J, Mottet C, Izcue A, Thompson C, Fanger A, Tannapfel A, Fontenot JD, Ramsdell F, Powrie F. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol. 2006; 177(9):5852-60. [Pubmed]

28. Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med. 2006; 203(11):2473-83. [Pubmed]

29. Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, Cua DJ, Powrie F, Cheever AW, Maloy KJ, Sher A. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med. 2006; 203(11):2485-94. [Pubmed]

30. Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D, Francisco L, Sharpe AH, Powrie F. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol. 2006; 177(7):4376-83. [Pubmed]

31. Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R, Robinson N, Buonocore S, Tlaskalova-Hogenova H, Cua DJ, Powrie F. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006; 25(2):309-18. [Pubmed]

32. Izcue A, Coombes JL, Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev. 2006; 212:256-71. [Pubmed]

33. Maloy KJ, Powrie F. Fueling regulation: IL-2 keeps CD4+ Treg cells fit. Nat Immunol. 2005; 6(11):1071-2. [Pubmed]

34. Annacker O, Coombes JL, Malmstrom V, Uhlig HH, Bourne T, Johansson-Lindbom B, Agace WW, Parker CM, Powrie F. Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J Exp Med. 2005; 202(8):1051-61. [Pubmed]

Powrie Mucosal Immunology Group

Group Leader is Fiona Powrie

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Outline of Research