Wild-type but not interferon-gamma-deficient T cells induce graft arterial disease in the absence of B cells.
OBJECTIVE
Interferon-gamma (IFN-gamma), 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-gamma in GAD.


METHODS
Wild-type (WT), IFN-gamma-/-, 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-gamma expression by infiltrating cells.


RESULTS
Moderate-to-severe GAD developed in WT recipient allografts, associated with abundant IFN-gamma expression by both infiltrating T cells and macrophages. No GAD developed in IFN-gamma-/- or in RAG-1-/- hosts, nor was any IFN-gamma expression evident. RAG-1-/- hosts receiving naïve WT or IFN-gamma-/- T cells (10(7)) 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-gamma expression by the transferred T cells and the host macrophages. Transfer of IFN-gamma-/- T cells induced neither GAD nor host macrophage IFN-gamma expression.


CONCLUSIONS
T cells, even in the absence of B cells, suffice to induce GAD, and T cell-derived IFN-gamma plays a critical role in GAD pathogenesis.
Furukawa
Yutaka
Y
Leducq Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, USA.
Cole
Sarah E
SE
Shah
Ravi V
RV
Fukumoto
Yoshihiro
Y
Libby
Peter
P
Mitchell
Richard N
RN
D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D006083:Graft Occlusion, Vascular / Q000276:immunology*; D016027:Heart Transplantation; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
D007371:Interferon-gamma