CXCL12 Induction of Inducible Nitric Oxide Synthase in Human CD8 T Cells
Received 27 May 2008; received in revised form 20 August 2008; accepted 26 August 2008.
Background
We reported previously that inducible nitric oxide synthase (iNOS) expression in graft-infiltrating human T cells that is confined to the bystander population contributes to T- cell–mediated rejection of allograft arteries in a humanized mouse model. Herein we examine whether CXCL12, a chemokine thought to contribute to recruitment of bystander T cells, induces iNOS in human CD8 T cells.
Methods
Human CD8 T cells were treated with CXCL12 and iNOS expression was examined. Also, human allograft arteries were immunohistochemically stained for iNOS and CD8, and adjacent sections stained for CXCL12 to determine their localization in human tissues.
Results
Resting human CD8 and CD4 T cells expressed the CXCR4, but not the CXCR7, receptor for CXCL12. Treatment with CXCL12 induced expression of both iNOS mRNA and protein in primary human CD8 T cells in a dose-dependent manner, but had no effect on CD4 T cells. Induction of iNOS expression in CD8 T cells was mediated by increased gene transcription. T-cell-receptor (TCR)-activated CD8 T cells rapidly downregulated CXCR4, which coincided with diminished ability of CXCL12 to induce iNOS in activated T cells. iNOS expression in infiltrating human CD8 T cells was spatially associated with CXCL12 expression both in the humanized mouse model of allograft artery rejection and in clinical specimens of coronary arteries displaying allograft vasculopathy.
Conclusions
CXCL12 induces iNOS expression in human CD8 T cells and this response may contribute to allograft rejection.
aDepartment of Immunobiology, Yale University School of Medicine, New Haven, Connecticut
bDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
cDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
dDepartment of Pathology, Yale University School of Medicine, New Haven, Connecticut
eDepartment of Dermatology, Yale University School of Medicine, New Haven, Connecticut
Reprint requests: Jordan S. Pober, MD, PhD, Department of Immunobiology, Yale University School of Medicine, 10 Amistad Street, Room 401D, New Haven, CT 06520-8089. Telephone: 203-737-2292. Fax: 203-737-2293
Supported by the National Institutes of Health (Grant HL070295 to J.S.P., and G.T., and Grant P01-HL56091 to W.M.B.), a postdoctoral fellowship from the Canadian Institutes of Health Research (J.C.C.), and a research fellowship from the International Society for Heart and Lung Transplantation (J.C.C.).
ABSTRACT