T-helper 17 (Th17) cells have been widely implicated as drivers of autoimmune disease. In particular, Th17 cytokine plasticity and acquisition of an interleukin-17A(+)(IL-17A(+)) interferon gamma(IFN gamma)(+) cytokine profile is associated with increased pathogenic capacity. Donor Th17 polarization is known to exacerbate graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT); however, donor Th17 cytokine coexpression and plasticity have not been fully characterized. Using IL-17 "fate-mapping" mice, we identified IL-6-dependent Th17 cells early after allo-SCT, characterized by elevated expression of proinflammatory cytokines, IL-17A, IL-22, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor. This population did not maintain lineage fidelity, with a marked loss of IL-17A and IL-22 expression late posttransplant. Th17 cells were further segregated based on IFN gamma coexpression, and IL-17A(+)IFN gamma(+) Th17 displayed an enhanced proinflammatory phenotype. Th17 cytokine plasticity and IFN gamma production were critically dependent upon donor-derived IL-12p40, and cyclosporine (CsA) treatment regulated this differentiation pathway. This observation was highly concordant with clinical samples from allo-SCT recipients receiving CsA-based immune suppression where although the IFNgnegative- Th17 subset predominated, IFN gamma(+)-Th17 cells were also present. In sum, Th17 polarization and ensuing differentiation are mediated by sequential inflammatory signals, which are modulated by immunosuppressive therapy, leading to distinct phenotypes within this lineage.
|Authors||Gartlan, Kate H.; Varelias, Antiopi; Koyama, Motoko; Robb, Renee J.; Markey, Kate A.; Chang, Karshing; Wilkinson, Andrew N.; Smith, David; Ullah, Md Ashik; Kuns, Rachel D.; Raffelt, Neil C.; Olver, Stuart D.; Lineburg, Katie E.; Teal, Bianca E.; Cheong, Melody; Teng, Michele W. L.; Smyth, Mark J.; Tey, Siok-Keen; MacDonald, Kelli P. A.; Hill, Geoffrey R.|
|Funding Body||Rio Tinto Ride to Conquer Cancer|