A Critical Role for Donor-Derived IL-22 in Cutaneous Chronic GVHD

摘要

Graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after allogeneic stem cell transplant (allo-SCT). Prevention and treatment of GVHD remains inadequate and commonly leads to end-organ dysfunction and opportunistic infection. The role of IL-17 and IL-22 in GVHD remains uncertain, due to an apparent lack of lineage fidelity and variable and contextually determined protective and pathogenic effects. We demonstrate that donor T-cell-derived IL-22 significantly exacerbates cutaneous chronic GVHD, and that IL-22 is produced by highly inflammatory donor CD4⁺ T-cells post-transplant. IL-22 and IL-17A derive from both independent and overlapping lineages, defined as Th22 and IL-22⁺Th17 cells. Donor Th22 and IL-22⁺Th17 share a similar IL-6-dependent developmental pathway and whilst Th22 arise independently of the IL-22⁺Th17 lineage, IL-17 signaling to donor Th22 directly promotes their development in allo-SCT. Importantly, while both IL-22 and IL-17 mediate skin GVHD, Th17-induced chronic GVHD can be attenuated by IL-22 inhibition in preclinical systems. In the clinic, high levels of both IL-17A and IL-22 expression are present in the skin of GVHD patients after allo-SCT. Together, these data demonstrate a key role for donor-derived IL-22 in chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation.