IL-27 Receptor Signaling on T cells Augments GVHD Severity through Enhancing Th1 Responses

IL-27 is a heterodimeric cytokine comprised of IL-27p28 and EBI3. As a relatively new member of the IL-12 family, the biological mechanisms associated with the role of IL-27 in the immune response are ambiguous, displaying both proinflammatory and suppressive functions that seem to be dependent on the disease model. A recent report demonstrates that pharmacological blockade of IL-27p28 alleviates graft-versus-host disease (GVHD) in mice. However, the specific role of the IL-27Rα/gp130 signaling complex that forms the IL-27 receptor (IL-27R) on T cells has not been well characterized in the context of allogeneic hematopoietic stem cell transplantation (allo-HCT). Here, we demonstrate that IL-27Rα expression on T cells exacerbates GVHD after allo-HCT, which was consistent across 3 different MHC- mismatched murine models of allo-HCT. Expression of IL-27Rα on T cells was required for acquisition of optimal Th1 effector function and subsequent inhibition of Th2 and T regulatory subsets after allo-HCT. Furthermore, administration of IL-27significantly increased mortality after allo-HCT; suggesting that the suppressive functions linked to IL-27 in T cell responses may be relatively modest in this model. Hence, IL-27Rα signaling on T cells promotes the development of GVHD.