Gartlan, K.Bommiasamy, H.Paz, K.Wilkinson, A.Owen, M.Reichenbach, D.Banovic, T.Wehner, K.Buchanan, F.Varelias, A.Kuns, R.Chang, K.Fedoriw, Y.Shea, T.Coghill, J.Zaiken, M.Plank, M.Foster, P.Clouston, A.Blazar, B.et al.2018-05-142018-05-142018American Journal of Transplantation, 2018; 18(4):810-8201600-61351600-6143http://hdl.handle.net/2440/112052Graft-versus-host disease (GVHD) is the major cause of nonrelapse morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). Prevention and treatment of GVHD remain inadequate and commonly lead to end-organ dysfunction and opportunistic infection. The role of interleukin (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 posttransplantation. IL-22 and IL-17A derive from both independent and overlapping lineages, defined as T helper (Th)22 and IL-22⁺ Th17 cells. Donor Th22 and IL-22⁺ Th17 cells share a similar IL-6-dependent developmental pathway, and while Th22 cells 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 patients with GVHD after allo-SCT. Together, these data demonstrate a key role for donor-derived IL-22 in patients with chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation.en© 2017 The American Society of Transplantation and the American Society of Transplant SurgeonsT cell biologybasic (laboratory) research/sciencebone marrow/hematopoietic stem cell transplantationbronchiolitis obliterans (BOS)cytokines/cytokine receptorsgraft-versus-host disease (GVHD)immunobiologylymphocyte biology: differentiation/maturationJournal article003008634810.1111/ajt.145130004288444000072-s2.0-85044672555370741