Introduction: Graft-versus-host disease (GVHD) is a major cause of allogeneic stem cell transplant (allo-SCT) related morbidity and mortality. Chronic manifestations such as cutaneous GVHD are very difficult to treat, commonly resulting in impaired wound healing, chronic pain and progressive restriction of joint mobility. Moreover, GVHD itself and the immunosuppressive therapy required to manage disease, results in high levels of opportunistic infection and mortality. Both IL-17 and IL-22 have been reported to drive skin GVHD, but the interplay between these cytokines is poorly understood.

Results: Here we show that IL-22 is produced by highly pro-inflammatory donor CD4⁺ T cells post-transplant and that IL-22 and IL-17 are derived from both independent and overlapping sources within this population. Th17 and Th22 share a similar developmental pathway via IL-6 early post-transplant, and whilst Th22 arise independently of Th17 lineage, IL-17A/F signalling in donor T cells promotes Th22 development. Donor-derived IL-22 drives skin GVHD as does donor IL-17, however Th17 induced pathology can be blocked by targeting IL-22. Clinically, unlike IL-17A, IL-22 is not systemically dysregulated late post transplant, but both IL-17A and IL-22 are significantly elevated in skin GVHD tissue.

Conclusions: This study confirms a pathogenic role for IL-22 in cutaneous GVHD and reveals previously unrecognised interplay between Th17 and Th22 development post-transplant. Together, these data highlight potential therapeutic approaches for targeting the Th17/Th22 differentiation axis to treat/prevent skin GVHD.