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Differential Requirement for IFN- in CTL Maturation in Acute Murine Graft-versus-Host Disease¹

Roman Puliaev^*, Phuong Nguyen^*, Fred D. Finkelman^2, and Charles S. Via^2,3,*

^* Research Service, Baltimore Veterans Affairs Medical Center, and Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and Immunology Division, Veterans Affairs Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45267

Although IFN- 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-, using IFN--deficient donors and administering anti-IFN- mAb, suppressed B cell elimination, down-regulated TNF- 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- independent, these observations indicate that IFN- elimination only partially blocks CTL development. IFN- 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- elimination only partially inhibited perforin gene expression and perforin-mediated CTL activity. The contributions of IFN- to CTL development were indirect, because IFN- 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- (perforin knockout donor cells and anti-IFN- mAb) converted AGVHD to CGVHD. Thus, both IFN--dependent induction of Fas/FasL and IFN--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.

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