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Roman Puliaev, Phuong Nguyen, Fred D Finkelman, Charles S Via, Differential Requirement for IFN-γ in CTL Maturation in Acute Murine Graft-versus-Host Disease, The Journal of Immunology, Volume 173, Issue 2, July 2004, Pages 910–919, https://doi.org/10.4049/jimmunol.173.2.910
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Abstract
Although IFN-γ is the archetypal Th1 cytokine, its role in CTL maturation is uncertain. We used an in vivo mouse model of CTL development, parent-into-F1 acute graft-vs-host disease (AGVHD), to evaluate this issue. In AGVHD, transfer of naive parental T cells into F1 hosts stimulates the development of allospecific CTL effectors that eliminate host lymphocytes, particularly B cells. Complete elimination of IFN-γ, using IFN-γ-deficient donors and administering anti-IFN-γ mAb, suppressed B cell elimination, down-regulated ΤNF-α production, and enhanced Th2 cytokine production, but did not allow the B cell expansion characteristic of chronic GVHD (CGVHD). Because complete CTL inhibition results in full-blown CGVHD that is IFN-γ independent, these observations indicate that IFN-γ elimination only partially blocks CTL development. IFN-γ elimination did not inhibit donor T cell engraftment or activation in the AGVHD model, but almost completely blocked Fas/Fas ligand (FasL) gene expression, protein up-regulation, and Fas/FasL-mediated CTL killing. In contrast, IFN-γ elimination only partially inhibited perforin gene expression and perforin-mediated CTL activity. The contributions of IFN-γ to CTL development were indirect, because IFN-γ receptor-deficient donor cells differentiated normally into allospecific CTLs. Consistent with the view that the Fas/FasL and perforin pathways each mediate CTL killing in AGVHD, the absence of both perforin and IFN-γ (perforin knockout donor cells and anti-IFN-γ mAb) converted AGVHD to CGVHD. Thus, both IFN-γ-dependent induction of Fas/FasL and IFN-γ-independent induction of perforin contribute to CTL-mediated elimination of host B cells in AGVHD. Suppression of both pathways is required for typical CGVHD development.
