Gitta Stockinger: Projects

Plasticity of immune effector cells (MRC funded)

Since the discovery of Th1 and Th2 effector T cell subsets 20 years ago, numerous T cell subsets were added to the list. It is unclear how many effector T cell subsets there may be and to what degree their characteristics are fixed or flexible. Furthermore, it has become increasingly clear over the last couple of years that a 'parallel universe' of innate lymphoid cells exists that adopt functional specialisation similar to the T cell subsets.

We are using cytokine 'fate' reporter models to facilitate visualisation and isolation of cells that have committed to particular cytokine expression to study their plasticity in different inflammatory models in vivo. The IL-17 fate reporter mouse established the extensive plasticity of Th17 cells in autoimmunity with a tendency to deviate towards a Th1 like profile and the acquisition of additional cytokines involved in pathology driven by IL-23 (Hirota et al. 2011). However, in the mucosal environment of Peyer's patches Th17 cells adopt the profile of follicular helper T cells and support the induction of IgA producing germinal center B cells (Hirota et al 2013).

Figure 1

Figure 1. Hypothetical model for the function of IL-9 in regulation of ILC2. (Click to view larger image)

The IL-9 fate reporter surprisingly revealed that innate lymphoid cells (ILC2) are the major producers of this cytokine in vivo and play an important role during inflammatory responses in the lung (Wilhelm et al 2011). IL-9 is an essential autocrine amplifier of ILC2 that promotes their survival and functional activity in promoting tissue repair in the recovery phase of helminth-induced lung infection (Turner et al 2013).

IL-9 production by ILC2 is induced by damaged ephithelial cells and promotes ILC2 survival as well as IL-5 and IL-13 production in an autocrine manner. In the adaptive phase of the immune response activated T cells provide IL-2, which enhances the production of IL-9 by ILC2. IL-5 and IL-13 promote classical features of the 'type 2' immune response like eosinophil recruitment, mucus production, and mast cell accumulation.

Selected Publications

Hirota, K; Turner, J-E; Villa, M; Duarte, JH; Demengeot, J; Steinmetz,OM and Stockinger, B (2013) Plasticity of TH17 cells in Peyer's patches is responsible for the induction of T cell-dependent IgA responses. Nature Immunology 14, 372-379

Hirota, K; Duarte, JH; Veldhoen, M; Hornsby, E; Li, Y; Cua, DJ; Ahlfors, H; Wilhelm, C; Tolaini, M; Menzel, U; Garefalaki, A; Potocnik, AJ and Stockinger, B (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nature Immunology 12, 255-264

Wilhelm, C; Hirota, K; Stieglitz, B; Van Snick, J; Tolaini, M; Lahl, K; Sparwasser, T; Helmby, H and Stockinger, B (2011) An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nature Immunology 12, 1071-1077 

Modulation of immune responses by the aryl hydrocarbon receptor (ERC funded)

We are investigating the physiological roles of the aryl hydrocarbon receptor (AhR) in the immune system. The AhR is a ligand dependent transcription factor best known for mediating the toxicity of dioxin. However, its strong evolutionary conservation suggests it has important physiological functions. We showed that in the CD4 T cell lineage AhR expression is restricted to the Th17 subset. Activation of AhR during Th17 development markedly increases the proportion of Th17 T cells and it essential for their production of IL-22 (Veldhoen et al .2008).

More recently Marc Veldhoen, now at the Babraham Institute, has shown the importance of AhR for the maintenance of intraepithelial lymphocytes that protect the intestinal barrier (Li et al 2011). We are using Cre-mediated deletion and reporting for AhR expression in different cell types to study AhR impact in various inflammatory models in vivo, focusing on barrier sites such as the skin and the lung. In collaboration with dermatologists (Frank Nestle, King's College and Ulrich Mrowietz, University Hospital Kiel) we are also investigating the potential role of the AhR pathway in psoriasis.

Figure 2.

Figure 2. (Click to view larger image)

Selected Publications

Veldhoen, M; Hirota, K; Westendorf, AM; 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

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 247, 629-640 


Physiological functions of the aryl hydrocarbon receptor in innate and adaptive immune responses (Wellcome Trust funded)

In this project we are building on the findings we obtained during the course of the ERC funded research (Topic 2) to extend our investigations on the physiological functions of AhR in the immune system by identifying AhR targets on DNA and protein level in different cell types and immunological conditions to gain mechanistic insight into how AhR works. Furthermore, we will focus on the physiological regulation of AhR signaling via metabolic enzymes such as CYP1A1 that are induced by AhR activation and subsequently metabolise the agonist in a negative feedback loop.

Figure 3

Figure 3. CYP1A1 reporter activity at baseline and after activation. a) Lung (A,B) and small intestine (D,E) from a Cyp1a1-Cre R26R eYFP reporter mouse stained for YFP (green), CD45 (blue) and DAPI (red) either untreated (panels A and D) or treated with 25mg/kl 3-methylcholanthrene (panels B and E). Lung and small intestine from a B6 control mouse (eYFP-ve) are shown in C and F. (Click to view larger image)