Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective means by which to treat a wide variety of diseases resulting from dysfunctional hematopoiesis due to a potent anti-tumor response known as the graft-versus-tumor (GVT) effect after chemotherapy and/or irradiation. The necessity of donor T cells to mediate GVT is offset by the consequential development of graft-versus-host disease (GVHD); a leading cause of mortality among allo- HCT recipients. The IL-12 family of cytokines signals through Janus Kinase 2 (JAK2) and is comprised of IL-12, IL-23, IL-27, IL-35 and IL-39. IL-12 (p35+p40) and IL-23 (p19+p40) have well documented proinflammatory functions responsible for Th1 differentiation and Th17 stabilization, respectively, and play critical roles in GVHD development. As such, we found that targeting p40 resulted in reduced GVHD. IL-12R and IL-23R also share a β-chain, IL-12Rβ1. While IL-23R is widely implicated in autoimmunity and GVHD, the role of IL-12Rβ1 remains much less defined. We found that donor splenocytes deficient for IL-12Rβ1 or IL-23R had an impaired ability to induce chronic GVHD (cGVHD). We also found a pathogenic role for IL-23R on donor T cells in acute GVHD (aGVHD); strikingly, a similar effect was not seen for IL-12Rβ1. Our studies then focused on determining how pharmacologically targeting IL-12/23p40 can be efficacious in reducing GVHD severity in experimental and clinical settings, yet also to explain why IL-12Rβ1 may be dispensable in aGVHD. The newest member of the IL-12 family, IL-39, is composed of IL-23p19 and EBI3. Given the cognate receptor for IL-39 includes IL-23R and gp130, we hypothesized that IL-39 may play a role in aGVHD. We detected significantly higher IL-39 in serum of mice with aGVHD compared to recipients of bone marrow alone (BMA) and cGVHD, providing a potential explanation for how IL-23R signaling could bypass IL-12β1. We also evaluated how JAK2 impacted GVHD. We found that T cell deficiency of JAK2 or neutralization via pacritinib significantly reduced mortality from GVHD. In summary, targeting IL-12 family signaling is an effective strategy to reduce GVHD. Further, future studies should focus on whether targeting IL-23/IL-39p19 is as effective as targeting IL-12/IL-23p40 in the clinic due to IL-39
