Wild-type but not interferon-γ-deficient T cells induce graft arterial disease in the absence of B cells

Abstract

Interferon-γ (IFN-γ), a cytokine produced primarily by T cells and by activated macrophages, plays a central role in the pathogenesis of graft arterial disease (GAD). This study investigated whether T cells can induce GAD in the absence of humoral alloresponses and whether activated macrophages or other host cell types can substitute as sources of IFN-γ in GAD. Methods: Wild-type (WT), IFN-γ−/−, or recombination-activating-gene-1−/− (RAG-1−/−; lacking mature T and B cells) mice received MHC II-disparate hearts. The grafts were harvested 8 weeks post-transplant and histological and immunohistochemical analyses, RNase protection assay (RPA), and flow cytometry were used to evaluate GAD lesions, infiltrating cell populations, and IFN-γ expression by infiltrating cells. Results: Moderate-to-severe GAD developed in WT recipient allografts, associated with abundant IFN-γ expression by both infiltrating T cells and macrophages. No GAD developed in IFN-γ−/− or in RAG-1−/− hosts, nor was any IFN-γ expression evident. RAG-1−/− hosts receiving naı̈ve WT or IFN-γ−/− T cells (107) after heart transplantation demonstrated no mature B cells but showed persistence of transferred T cells up to 8 weeks post-transplant. In the complete absence of B cells and alloantibody, transfer of WT T cells into RAG-1−/− recipients yielded GAD, with associated IFN-γ expression by the transferred T cells and the host macrophages. Transfer of IFN-γ−/− T cells induced neither GAD nor host macrophage IFN-γ expression. Conclusions: T cells, even in the absence of B cells, suffice to induce GAD, and T cell-derived IFN-γ plays a critical role in GAD pathogenesis.