Detailseite
Projekt
Investigating the impact of entheseal resident yd T lymphocytes on tissue remodeling in spondyloarthropathy via the IL-23 - IL-17 cytokine axis.
Antragsteller
Professor Dr. Immo Prinz
Fachliche Zuordnung
Immunologie
Rheumatologie
Rheumatologie
Förderung
Förderung von 2013 bis 2017
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 237394450
Spondyloarthritis is a common disease with a prevalence of 1-2% worldwide. It is emerging that perturbations of the IL-23 - IL-17 cytokine axis are associated with spondyloarthritis-related disease. Increasing evidence suggests that entheseal tissue is the primary initiating site of inflammation in ankylosing spondylitis. The enthesis is a specialized tissue at the interface of tendon and bone. A recent discovery by the group of Daniel Cua (Sherlock, JP et al., 2012 Nat Med. 18:1069-76) identified a so far unrecognized population of T lymphocytes residing in the enthesis. Their particular anatomical location, as well as their innate IL-23 receptor (IL-23R)+ and RAR-related orphan receptor yt (ROR-yt)+ phenotype make these cells prime suspects for the induction of enthesitis and entheseal bone remodeling. Indeed, systemic overabundance of IL-23 rapidly induced the production of inflammatory IL-17 family cytokines and led to a severe spondyloarthropathy in susceptible B10.RIII mice that phenocopied the human disease. We have now further investigated the populations of entheseal T cells. Using 2-photon laser scanning microscopy and a genetic fluorescent reporter model, we found a hitherto unknown population of yd T cells residing in the enthesis. These entheseal yd T cells were not motile but appeared to be tethered in a specialized anatomical niche. In this proposal, we aim at characterizing ontogeny, phenotype, and potentially inflammatory functions of these cells. We will establish to what extent entheseal yd T cells overlap with the enthesis-resident CD3+CD4–CD8– population of T cells described by Daniel Cua and colleagues. Furthermore, we aim at backcrossing our Tcrd-H2BeGFP reporter mice as well as a recently generated strain that is deficient for both highly homologous cytokines IL-17A and IL-17F from the less susceptible C57BL/6 towards the highly susceptible B10.RIII background. Establishing experimental spondyloarthropathy in those animals will allow us to thoroughly analyze the biology and pathophysiology of IL-17 cytokine producing entheseal yd T lymphocytes. Therefore, this proposal has considerable relevance for the development of novel therapeutic strategies that may specifically and locally target inflammatory yd T lymphocytes.
DFG-Verfahren
Schwerpunktprogramme
