Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

Kate H Gartlan; Antiopi Varelias; Motoko Koyama; Renee J Robb; Kate A Markey; Karshing Chang; Andrew N Wilkinson; David Smith; Md Ashik Ullah; Rachel D Kuns; Neil C Raffelt; Stuart D Olver; Katie E Lineburg; Bianca E Teal; Melody Cheong; Michele W L Teng; Mark J Smyth; Siok-Keen Tey; Kelli P A MacDonald; Geoffrey R Hill

doi:10.1182/bloodadvances.2016002980

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

Blood Adv. 2017 Jan 26;1(6):341-351. doi: 10.1182/bloodadvances.2016002980. eCollection 2017 Feb 14.

Authors

Kate H Gartlan^{1

2}, Antiopi Varelias^{1

2}, Motoko Koyama¹, Renee J Robb¹, Kate A Markey^{1

2

3}, Karshing Chang¹, Andrew N Wilkinson^{1

2}, David Smith¹, Md Ashik Ullah¹, Rachel D Kuns¹, Neil C Raffelt¹, Stuart D Olver¹, Katie E Lineburg¹, Bianca E Teal¹, Melody Cheong¹, Michele W L Teng¹, Mark J Smyth^{1

2}, Siok-Keen Tey^{1

2

3}, Kelli P A MacDonald¹, Geoffrey R Hill^{1

3}

Affiliations

¹ Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
² School of Medicine, University of Queensland, Herston, QLD, Australia; and.
³ Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Abstract

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 γ(IFNγ)⁺ 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 IFNγ coexpression, and IL-17A⁺IFNγ⁺ Th17 displayed an enhanced proinflammatory phenotype. Th17 cytokine plasticity and IFNγ 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 IFNγ-negative-Th17 subset predominated, IFNγ⁺-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.