MRC National Institute for Medical Research, London
Science for Health
A more detailed analysis of Th17 cells
31 January 2011
NIMR scientists have shown using a fate reporter for IL-17A that fate decisions of Th17 cells are shaped by different inflammatory conditions in vivo allowing distinct patterns of plasticity. The research is published in Nature Immunology.
CD4 helper T cells are an important part of the immune system, involved in activating and directing other immune cells. A longstanding paradigm in immunology classified effector CD4 T cells into subsets based on the expression of lineage defining transcription factors and characteristic cytokines. There are four major CD4 T cell subsets, termed Th1, Th2, Treg and Th17, each with distinct functional capacities. Th1 cells are important in the defence against intracellular pathogens, whereas Th2 cells respond to extracellular pathogens and Th17 cells are crucially involved in anti-fungal immune responses, but are also implicated in the pathogenesis of many autoimmune diseases. Treg on the other hand are important regulators preventing excessive effector responses against pathogens or self antigens.
Th17 produce interleukin-17 (IL-17) and they were classified most recently as a new effector CD4 T cells subset distinct from Th1 cells, which express their “signature cytokine” IFN-gamma, and Th2 cells, which are characterised by IL 4 production. Nevertheless, it became clear that Th17 cells displayed considerable developmental plasticity and readily acquired the capacity to produce IFN-gamma in addition to IL-17 or even completely shut off IL-17 production in vitro, explaining the initial erroneous assumption that these cells have diverged from a common Th1 precursor. With plasticity attributed mainly to in vitro generated Th17 cells, it remained a possibility that this was an artefact of tissue culture, resulting in a particular set of stimuli that seem to contribute to Th17 differentiation. Since Th17 cells are defined by the expression of their signature cytokine IL-17, loss of cytokine expression equates to loss of detection, so that it was not possible to unequivocally determine the developmental processes these cells underwent following their activation.
Gitta Stockinger (pictured) and Alexandre Potocnik, from NIMR’s Division of Molecular Immunology, have generated a Th17 reporter system that allows identification and fate mapping of these cells in vivo. They inserted Cre recombinase into the Il17a locus and crossed these mice to Rosa26-enhanced yellow fluorescence protein (eYFP) reporter mice, thus allowing identification of all IL 17-producing cells as well as enabling identification of their cellular progeny.
Using this method they have shown that eYFP expression in T cells is induced exclusively under Th17 conditions in vitro and - more importantly - in vivo. However, in vivo Th17 cells rapidly lost IL-17A expression in the course of inflammatory immune responses similar to what was seen during Th17 differentiation in vitro. Fate determination of eYFP+ ‘ex-Th17’ cells under different inflammatory conditions in vivo revealed surprising differences in their developmental plasticity. For instance, chronic inflammatory conditions in a model for central nervous system inflammation (experimental autoimmune encephalitis, EAE) resulted in rapid downregulation of IL-17 and acquisition of IFN-gamma as well as other pro-inflammatory cytokines that were previously associated with Th17 cells. It was found that more than 95% of all inflammatory cytokines produced in the inflamed spinal cord were derived from eYFP+ ‘ex-Th17’ cells. In contrast an acute and rapidly resolved skin infection with the fungal pathogen Candida albicans did induce Th17 plasticity.
Thus, IL-17A fate reporter mice constitute a valuable tool for dissection of effector cytokine programs that may have originated initially from Th17 cells. This will facilitate the mechanistic analysis of the role of inflammatory drivers that shape decision-making by effector T cells.
“We think our fate reporter data finally reconciles several controversial findings in the Th17 field especially with regard to their role in autoimmune diseases such as EAE (a mouse model for multiple sclerosis). They further reveal that developmental plasticity towards a Th1 profile is not an automatic pathway Th17 cells initiate, since they show a completely different behaviour in another inflammatory model - the cutaneous Candida infection. Most importantly we clearly demonstrate that in EAE the vast majority of pathogenic T cells originate from Th17 cells which might help in targeting therapeutic strategies more precisely to the T cells subset which is causal for the inflammatory process”.
Gitta Stockinger and Alexandre Potocnik
Original article
Keiji Hirota, João H Duarte, Marc Veldhoen, Eve Hornsby, Ying Li, Daniel J Cua, Helena Ahlfors, Christoph Wilhelm, Mauro Tolaini, Ursula Menzel, Anna Garefalaki, Alexandre J Potocnik & Brigitta Stockinger (2011)Fate mapping of IL-17 producing T cells in inflammatory responses
Nature Immunology Epub ahead of print. Publisher abstract
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