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IL-23-dependent γδ T cells produce IL-17 and accumulate in enthesis, aortic valve, and ciliary body

Arthritis Rheumatol. 2016 Apr 25. doi: 10.1002/art.39732. [Epub ahead of print]

Authors/Editors: Reinhardt A, Yevsa T, Worbs T, Lienenklaus S, Sandrock I, Oberdörfer L, Korn T, Weiss S, Förster R, Prinz I.
Publication Date: 2016

reinhardt_05_2016

Abstract

OBJECTIVE:
Spondyloarthropathies (SpA) are a group of rheumatic diseases comprising ossification and inflammation of entheseal tissue, the region where tendon attaches onto bone. Interleukin (IL)-23 is involved in the pathogenesis of SpA by acting on IL-23 receptor (IL-23R) expressed on enthesis-resident lymphocytes. Upon IL-23 binding, CD3+ CD4- CD8- tissue-resident lymphocytes secrete IL-17A and IL-22, leading to inflammation, bone loss, and ossification. Still, our knowledge about enthesis-resident lymphocytes remains fragmentary, in particular the contribution of entheseal γδ T cells is not clear.

METHODS:
We used two-photon microscopy and flow cytometric analysis of entheseal lymphocytes from C57BL/6, Tcrd-H2BeGFP, Rorc-GFP and IL-23R-eGFP mice. To analyze entheseal γδ T cells in IL-23-induced inflammation, Tcrd-H2BeGFP mice were crossed to the susceptible B10.RIII background. Hydrodynamic injection of IL-23 minicircle DNA was performed for overexpression of IL-23 and induction of inflammation. Light-sheet fluorescence microscopy was applied to visualize arthritic inflammation.

RESULTS:
Activated Vγ6+ CD27- γδ T cells are abundant in non-inflamed entheseal tissue and constitute the large majority of RORγt+ IL-23R+ enthesis-resident lymphocytes. Fetal thymus-dependent γδ T cells are the main source of IL-17A at the enthesis. Under inflammatory conditions, γδ T cells increase in numbers at the Achilles tendon enthesis, aortic root, and adjacent to the ciliary body.

CONCLUSION:
Entheseal γδ T cells are derived from fetal thymus and are maintained as self-renewing tissue-resident cells. As main IL-17A producers within tissues exposed to mechanical stress including enthesis, γδ T cells are key players in the pathogenesis of IL-23-induced local inflammation.

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