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*
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.
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