Fiona Powrie’s
Mucosal Immunology Group

 

 

 

 

 

 

Professor Fiona Powrie

Sir William Dunn School of Pathology

University of Oxford

South Parks Rd

Oxford OX1 3RE

Phone: (01865) 285489

Fax: (01865) 275591

 

Outline of Research

Projects in the lab

Studentship position available

Lab Members

Publications

 

 

 

 

 

 

 

 

Outline of
Research

 

 

 

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 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 govern T cell responsiveness and non responsiveness in the intestine, identification of immune regulatory mechanisms (with particular emphasis on the role of T cell subsets and their cytokines) which lead to the development of tolerance to intestinal antigens and how a breakdown in these mechanisms may lead to the development of inflammatory bowel disease.

 

 

 

 

 

 

 

 

 

 

 

 

Projects in

the 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.

 

Genetic models of intestinal inflammation*

As part of the European Union funded Research and Training network Innovative Models for Functional Genomics in Immunology we are developing novel models of intestinal inflammation using state of the art gene-targeting strategies. See http://www.humgen.nl/IMDEMI/index.html for further details of the partner labs.

 

Genetic susceptibility alleles in colon cancer*

Using a model of colon cancer we are performing genetic mapping studies to identify genes that influence the development of this disease.

 

Regulatory T cell function

   Cellular: Our studies have also shown that functionally specialized populations of regulatory T cells (Treg) play an important role in maintaining intestinal homeostasis. Thus, naturally arising CD4+CD45RBlowCD25+ 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. This may be related to DC mediated tissue imprinting as we have recently identified a functionally distinct DC subset that it abundant in the intestine and plays a role in Treg function. 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.

   Molecular: As part of Eurothymaide an EU funded integrated project we are identifying genetic pathways involved in regulatory T cell function (Website www.eurothymaide.org).

 

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

 

 

 

 

 

 

Costaining of Foxp3 and IL-10 on human appendix tissue. Left, Costaining of Foxp3, IL-10, and DAPI showing IL-10-positive cells within the germinal center (GC) and subepithelial dome (SED) close to the epithelium (E). Detail of Foxp3+IL-10+ cells within the subepithelial dome area are also shown. Right, Costaining of Foxp3, IL-10, and CD3.

Detail shows IL-10+CD3+Foxp3+ cells as well CD3+Foxp3+ cells that are in close contact with IL-10+CD3–Foxp3– cells.

 

 

 

 

 Studentship position available

 

To apply, please follow this link:

http://www.ndm.ox.ac.uk/project-list/doctoral-projects (Ref number 215)

 

Investigation of the IL-23/Th17 axis in inflammatory bowel disease

 

       The inflammatory bowel diseases are chronic debilitating inflammatory diseases (IBD) of the intestine with no known cure. In IBD the normal peaceful relationship between the immune system and bacteria in the intestine breaks down with the development of damaging inflammatory responses in the bowel. Work from the Powrie lab has shown that intestinal homeostasis is a delicate balance between effector and regulatory T cell responses.

       Studies in model systems have revealed a pivotal role for the cytokine IL-23 in the development of chronic intestinal inflammation. IL-23 plays an important role in  promoting Th17 responses in vivo and suppressing regulatory T cell responses. In addition IL-23 orchestrates T cell independent innate immunity in the gut. There is evidence that Th17 responses are increased in patients with IBD and several genes in the IL-23/Th17 pathway confer risk to IBD. Despite these data, little is known about the IL-23 pathway in the human intestine in health and disease.

       This aim of this Project is to dissect the cellular and molecular pathways that control IL-23 production and function in the intestine and how this changes in inflammatory bowel disease. Innate immune stimuli that promote IL-23 will be analysed as well as the major myeloid cell types that contribute to IL-23 in the human gut. The effects of IL-23 on human intestinal T cells and innate cells will also be assessed including activation of downstream signalling pathways.

 

Training opportunities:

       The project will be performed in the newly established Translational  Gastroenterology Unit headed by Professor Powrie. This Unit brings together basic scientists, clinician scientists and clinical gastroenterologists with the aim of translating fundamental findings in mucosal immunology into the development of novel treatments for inflammatory bowel disease. The Project will utilise state of the art approaches to cellular and molecular immunology including FACS analysis, in vitro assays of cell function, measurement of signalling pathways and confocal microscopy. The student will be exposed to basic science, translational medicine and clinical trials providing a strong muti-disciplinary approach. The group hold regular lab meetings and Journal Clubs providing training in critical analysis of the literature and presentation skills.

  

Selected References:

  1. Coombes, J.L., Siddiqui, K.R., Arancibia-Carcamo, C.V., Hall, J., Sun, C.M., Belkaid, Y., and Powrie, F. (2007). 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 204, 1757-1764.
  2. Uhlig, H.H., McKenzie, B.S., Hue, S., Thompson, C., Joyce-Shaikh, B., Stepankova, R., Robinson, N., Buonocore, S., Tlaskalova-Hogenova, H., Cua, D.J. and Powrie, F. (2006). Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309-318.
  3. Hue, S., Ahern, P., Buonocore, S., Kullberg, M.C., Cua, D.J., McKenzie, B.S., Powrie, F., and Maloy, K.J. (2006). Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 203, 2473-2483.
  4. Izcue, A., Hue, S., Buonocore, S., Arancibia-Carcamo, C.V., Ahern, P.P., Iwakura, Y., Maloy, K.J., and Powrie, F. (2008). Interleukin- 23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559-570.
  5. Izcue,A., Coombes,J. L.and Powrie F (2009). Regulatory Lymphocytes and Intestinal Inflammation. Annual Review of Immunology. Vol. 27: 313-338

 

 

 

 

 

 

 

 

Group Members

 

Mechanisms of intestinal inflammation

   Philip Ahern  Graduate student*

   Sofia Buonocore  Postdoctoral fellow*

   Alessandra Geremia  Clinical training fellow

   Thibault Griseri  Postdoctoral fellow

   Rose Szabady  Postdoctoral fellow

 

Genetics of colon cancer

   Olivier Boulard  Postdoctoral fellow*

   Stefanie Kirchberger  Postdoctoral fellow

 

 

 

   Chris Jenkins  Technician

 

*co-supervised by Dr Kevin Maloy (Lab Website)

 

Regulatory T cells

   Cellular

   Carolina Arancibia  Postdoctoral fellow

   Mark Asquith  Graduate student*

   Andrew Johnson  Graduate student

   Sophie Laffont-Pradines  Postdoctoral fellow

   Karima Siddiqui  Graduate student

   Michael Barnes  Graduate student*

 

 

 

 

Recent Publications

 

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

2.      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.

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

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

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

6.      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.

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

8.      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.

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

10.  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.

11.  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.

12.  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.

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

14.  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.

15.  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.

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

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

18.  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.

19.  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.

20.  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.

21.  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.

22.  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.

23.  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.

24.  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.

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

26.  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.

 

Older References

 

 

 

 

 

 
 
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                                                                               last update 05.11.09