Interleukin-23 receptor signaling by interleukin-39 potentiates T cell pathogenicity in acute graft-versus-host disease

IL-12 (p35/p40) and IL-23 (p19/p40) signal through IL-12R (IL-12R beta 2/beta 1) and IL-23R (IL-23R alpha/IL-12R beta 1), respectively, which can promote pathogenic T lymphocyte activation, differentiation, and function in graft-versus-host disease (GVHD). With the use of murine models of allogeneic hematopoietic cell transplantation (HCT), we found that IL-12R beta 1 on donor T cells was dispensable to induce acute GVHD development in certain circumstances, while IL-23R alpha was commonly required. This observation challenges the current paradigm regarding IL-12R beta 1 as a prerequisite to transmit IL-23 signaling. We hypothesized that p19/EBI3 (IL-39) may have an important role during acute GVHD. With the use of gene transfection and immunoprecipitation approaches, we verified that p19 and EBI3 can form biological heterodimers. We found that IL-39 levels in recipient serum positively correlated with development of acute GVHD in experimental models and in clinical settings, thereby implicating IL-39 in the pathogenesis of acute GVHD. Furthermore, we observed that human T cells can signal in response to IL-39. In chronic GVHD, IL-23R alpha and IL-12R beta 1 were similarly required for donor T cell pathogenicity, and IL-39 levels were not significantly different from controls without GVHD. Collectively, we identify a novel cytokine, IL-39, as a pathogenic factor in acute GVHD, which represents a novel potential therapeutic target to control GVHD and other inflammatory disorders.