Human spinal enthesis comparative biology of IL-17F and IL-17A reveals greater T-cell IL-17F induction and IL-23 regulation.

McDermott, N.; Altaie, A.; Macleod, T.; Bridgewood, C.; Loughenbury, P.; Dunsmuir, R.; Khan, A.; Borse, V.; Rao, A.; Manghera, A.; Shaw, S.; McGonagle, D.

Human spinal enthesis comparative biology of IL-17F and IL-17A reveals greater T-cell IL-17F induction and IL-23 regulation.

All Authors

McDermott, N.

Altaie, A.

Macleod, T.

Bridgewood, C.

Loughenbury, P.

Dunsmuir, R.

Khan, A.

Borse, V.

Rao, A.

Manghera, A.

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LTHT Author

Loughenbury, Peter
Khan, Almas
Borse, Vishal
Rao, Abhay
McGonagle, Dennis

LTHT Department

Orthopaedics
Spinal Surgery
Pain Services
Trauma & Related Services
Rheumatology
NIHR Leeds Biomedical Research Centre

Publication Date

2025

Item Type

Journal Article
Comparative Study

Abstract

Objective: Although IL-17F is important in psoriasis, the rudimentary biology of IL-17F in the human enthesis remains undefined. We aimed to characterise IL-23-dependent and independent IL-17F production from entheseal innate and adaptive T cells and determine the impact of IL-17F on entheseal stromal function and mesenchymal stem cell (MSC) osteogenesis. Methods: Anti-CD3 and anti-CD28 activated human spinal entheseal T cells were immunophenotyped using multi-parameter flow cytometry and a 36-marker Cytometry by Time-Of-Flight (CyTOF) with cytokine profiling, including IL-17A, IL-17F, and TNF (n = 10). IL-17A, IL-17F, and TNF stimulation of entheseal MSC stromal function was evaluated using RNA-seq and by measuring CCL20 protein expression following stimulation with TNF in combination with IL-17A or IL-17F. The osteogenic effects of IL-17A and IL-17F on MSC differentiation were assessed. Results: Inducible IL-17A and IL-17F expression was predominantly from CD4 T cells and CD4+CD25+ T cells, with higher levels of IL-17F at 72 hr. IL-23 significantly increased IL-17F (p <= 0.0001) but not IL-17A. Either IL-17A or IL-17F in combination with TNF dramatically upregulated CCL20 protein expression and substantially changed entheseal stromal transcriptome, with differences in gene expression and pathway activation seen between IL-17A or IL-17F stimulation. However, entheseal MSC osteogenesis was not significantly changed. Conclusions: There was differential induction of IL-17A and IL-17F from innate and adaptive entheseal T cells, with further significant IL-17F augmentation by IL-23, but not IL-17A. Furthermore, the synergistic effects of IL-17A or IL-17F and TNF on stromal function provide the basis for further enthesis IL-17F biology interrogation.