Graft-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.
Bibliographical noteFunding Information:
This work was supported by grants from the QIMR Berghofer, Cancer Council Queensland, the National Health and Medical Research Council (Australia), and the National Institutes of Health (P01 CA142106 and R01 CA166794). G.R.H. is a National Health and Medical Research Council Fellow.
© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons
- T cell biology
- basic (laboratory) research/science
- bone marrow/hematopoietic stem cell transplantation
- bronchiolitis obliterans (BOS)
- cytokines/cytokine receptors
- graft-versus-host disease (GVHD)
- lymphocyte biology: differentiation/maturation