Interleukin-23-Dependent γ/δ T Cells Produce Interleukin-17 and Accumulate in the Enthesis, Aortic Valve, and Ciliary Body in Mice.
The spondyloarthritides (SpA) are a group of rheumatic diseases characterized by ossification and inflammation of entheseal tissue, the region where tendon attaches to bone. Interleukin-23 (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. Knowledge about enthesis-resident lymphocytes remains fragmentary, and the contribution of entheseal γ/δ T cells in particular is not clear. This study was undertaken to investigate the presence of γ/δ T cells in the enthesis.



We used 2-photon microscopy and flow cytometry to analyze entheseal lymphocytes from C57BL/6, Tcrd-H2BeGFP, Rorc-GFP, and IL-23R-eGFP mice. To analyze entheseal γ/δ T cells in IL-23-induced inflammation, Tcrd-H2BeGFP mice were crossed with mice of 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 used to visualize arthritic inflammation.



Activated Vγ6+CD27- γ/δ T cells were abundant in uninflamed entheseal tissue and constituted the large majority of retinoic acid receptor-related orphan nuclear receptor γt (RORγt)+IL-23R+ enthesis-resident lymphocytes. Fetal thymus-dependent γ/δ T cells were the main source of IL-17A at the enthesis. Under inflammatory conditions, γ/δ T cells increased in number at the Achilles tendon enthesis, aortic root, and adjacent to the ciliary body.



Entheseal γ/δ 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, γ/δ T cells are key players in the pathogenesis of IL-23-induced local inflammation.
Hannover Medical School, Hannover, Germany.
Annika
A
Reinhardt
Hannover Medical School, Hannover, Germany.
Tetyana
T
Yevsa
Hannover Medical School, Hannover, Germany.
Tim
T
Worbs
Hannover Medical School, Hannover, Germany.
Stefan
S
Lienenklaus
Hannover Medical School, Hannover, Germany.
Inga
I
Sandrock
Hannover Medical School, Hannover, Germany.
Linda
L
Oberdörfer
Klinikum rechts der Isar, Technische Universität München and Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
Thomas
T
Korn
Hannover Medical School, Hannover, Germany.
Siegfried
S
Weiss
Hannover Medical School, Hannover, Germany.
Reinhold
R
Förster
Hannover Medical School, Hannover, Germany. prinz.immo@mh-hannover.de.
Immo
I
Prinz
D000125:Achilles Tendon / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000843:Ankle Joint / Q000276:immunology / Q000473:pathology; D001021:Aortic Valve / Q000276:immunology* / Q000473:pathology; D002924:Ciliary Body / Q000276:immunology* / Q000473:pathology; D000070676:Enthesopathy / Q000276:immunology / Q000473:pathology; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics; D020381:Interleukin-17 / Q000276:immunology; D053759:Interleukin-23 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D025242:Spondylarthropathies / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D055114:X-Ray Microtomography; D000097043:Interleukin-22
D049452:Green Fluorescent Proteins; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000097043:Interleukin-22; C098680:Il17a protein, mouse; C539901:Rorc protein, mouse