Plasticity of immune effector cells
In this Crick-funded project, 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). Ongoing studies are focused on determining the mechanisms underlying Th17 to Tfh plasticity as well as the mechanism underlying their help for IgA responses.
Figure 1: Th17 cell plasticity can be beneficial or detrimental depending on tissue site and context. In the small intestine, Th17 cells may convert into IL-10 producing 'ex Th17' Tr1 cells under the influence of TGF-β1 via Smad3 and AhR. In Peyer's patches Th17 cells acquire a follicular helper T cell phenotype and provide help for induction of IgA. During Helicobacter hepaticus infection or infection with Citrobacter rodentium newly induced colonic Th17 cells develop plasticity towards IFN-γ producing 'exTh17' Th1 cells. A similar IL-23-dependent Th17 plasticity is observed in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). Here 'exTh17' Th1 cells produce a broader spectrum of cytokines, including TNF-α, GM-CSF and IFN-γ.