Host-Derived Interleukin-18 Differentially Impacts Regulatory and Conventional T Cell Expansion During Acute Graft-Versus-Host Disease

Interleukin (IL)-18 stimulates T helper 1 (Th1) and Th2-mediated immune responses, and has been shown to modulate acute graft-versus-host disease (aGVHD). It is still unknown whether increased IL-18 levels during aGVHD are of host or donor origin, and how the absence of IL-18 has an impact on migration and expansion of conventional CD4+CD25−(Tconv) and CD4+CD25+ regulatory (Treg) T cells in vivo. By utilizing IL-18 gene-deficient donor versus recipient animals we found that the major cytokine production during the early phase of aGVHD induction was recipient derived, whereas donor hematopoietic cells contributed significantly less. By generating IL-18−/− luciferase transgenic mice we were able to investigate the impact of IL-18 on Tconv and Treg expansion and trafficking with in vivo bioluminescence imaging. Although migration to secondary lymphoid organs did not have a significantly impact from the absence of host IL-18, Tconv but not Treg expansion increased significantly. Absence of host IL-18 production translated into lower IFN-γ levels in the early phase after transplantation. We conclude that host-derived IL-18 is a major factor for IFN-γ production that may have a protective effect on CD4+-mediated aGVHD, but is nonessential for Treg expansion in an allogeneic environment.