Potential Role of IL-39 in the Development of Gvhd

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective means by which to treat a wide variety of diseases resulting from hematological dysfunction. However, the development of graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality post transplantation. The IL-12 family of cytokines is comprised of IL-12, IL-23, IL-27, IL-35, and potentially IL-39. IL-12 family members are unique in that each cytokine and cognate receptor is comprised of heterodimers in which either the a or b subunit is shared among the others. 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. IL-12R and IL-23R share a β-chain (IL-12Rβ1) yet use distinct α-chains to mediate their respective receptor signaling. While both IL-12R and IL-23R are widely implicated in inflammatory disorders, the role of IL-12Rβ1 in this context remains much less defined. We therefore studied the impact of eliminating the common IL-12Rβ1 chain or the unique IL-23Rα chain in T cells on GVHD using murine models of allogeneic bone marrow transplantation (BMT). In agreement with previous publications, we found a pathogenic role for IL-23Rα on donor T cells in aGVHD. Strikingly, a similar effect was not seen for IL-12Rβ1 (Figure 1A, B). These data suggest that that IL-23Rα contributes to GVHD pathogenesis via a pathway independent of IL-12Rβ1. To confirm that functional differences existed between T cells deficient for IL-23Rα or IL-12Rβ1 in GVHD, we assessed cytokine profiles of these T cells in target organs 14 days post-BMT. We found that, while production of IFNγ and IL-17 in the spleen was similarly decreased in both cohorts, GM-CSF production by CD4+ T cells was reduced exclusively in T cells deficient for IL-23Rα. Further, a significant reduction of IFNγ and GM-CSF in target organs, such as the liver and gut, was only observed in T cells deficient for IL-23Rα. The newest member of the IL-12 family, IL-39, was recently shown to contribute to SLE pathogenesis; this cytokine has been described to be composed of IL-23p19 and EBI3. Given the cognate receptor for IL-39 includes IL-23Rα and gp130, we hypothesized that IL-39 may play a role in aGVHD as this would explain why IL-12Rβ1 is dispensable. To validate that p19 and EBI3 can form a heterodimer, we transfected SV40 cells with vectors containing control, IL-23p19,