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Thymic Dendritic Cells Express Inducible Nitric Oxide Synthase and Generate Nitric Oxide in Response to Self- and Alloantigens¹

Sistiana Aiello^*, Marina Noris^*, Giampiero Piccinini^*, Susanna Tomasoni^*, Federica Casiraghi^*, Samantha Bonazzola^*, Marilena Mister^*, Mohamed H. Sayegh and Giuseppe Remuzzi^2,*,

^* Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and Division of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Largo Barozzi 1, Bergamo, Italy

Thymocytes maturing in the thymus undergo clonal deletion/apoptosis when they encounter self- or allo-Ags presented by dendritic cells (DCs). How this occurs is a matter of debate, but NO may play a role given its ability of inducing apoptosis of these cells. APC (a mixed population of macrophages (M) and DCs) from rat thymus expressed high levels of inducible NO synthase (iNOS) and produced large amounts of NO in basal conditions whereas iNOS expression and NO production were very low in thymocytes. Analysis by FACS and by double labeling of cytocentrifuged preparations showed that DCs and M both express iNOS within APC. Analysis of a purified preparation of DCs confirmed that these cells express high levels of iNOS and produce large amounts of NO in basal conditions. The capacity of DCs to generate NO was enhanced by exposure to rat albumin, a self-protein, and required a fully expressed process of Ag internalization, processing, and presentation. Peptides derived from portions of class II MHC molecules up-regulate iNOS expression and NO production by DCs as well, both in self and allogeneic combinations, suggesting a role of NO in both self and acquired tolerance. We also found that NO induced apoptosis of rat double-positive thymocytes, the effect being more evident in anti-CD3-stimulated cells. Altogether, the present findings might suggest that DC-derived NO is at least one of the soluble factors regulating events, in the thymus, that follow recognition of self- and allo-Ags.