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Regulation of CD8 Expression in Mast Cells by Exogenous or Endogenous Nitric Oxide1

We recently reported a novel CD8 molecule on rat alveolar macrophages and peritoneal mast cells (PMC). However, little is known about the regulation of CD8 expression and function on these cells. We investigated the regulation of CD8 expression on PMC by NO, because NO can regulate inflammatory responses and also because anti-CD8 Ab stimulates inducible NO synthase and NO production by PMC and alveolar macrophages. Ligation of CD8α on PMC with Ab (OX8) induced CD8α mRNA expression after 3–6 h, and flow cytometry demonstrated that OX8 treatment increased CD8α protein expression compared with PMC treated with isotype control IgG1. To test whether NO mediates the up-regulation of CD8α, we used the NO donor S-nitrosoglutathione (500 μM) and NO synthase inhibitors (NG-monomethyl-l-arginine and NG-nitro-l-arginine methyl ester; 100 μM). S-nitrosoglutathione up-regulated both mRNA and protein expression of CD8α in PMC compared with that in sham-treated cells, while NO synthase inhibitors down-regulated OX8 Ab-induced CD8α expression. To investigate how NO regulates CD8 expression on PMC, we examined the cGMP-dependent pathway using 8-bromo-cGMP (2 mM) and the guanylate cyclase inhibitor, 1H-oxadiazoloquinoxalin-1-one (20 μM). 8-Bromo-cGMP up-regulated CD8 expression, whereas 1H-oxadiazoloquinoxalin-1-one down-regulated its expression. Thus, ligation of CD8 up-regulates CD8 expression on PMC, a response mediated at least in part by NO through a cGMP-dependent pathway. The significance of this up-regulation of CD8α on mast cells (MC) is unclear, but since ligation of CD8 on MC with OX8 Ab can alter gene expression and mediator secretion, up-regulation of CD8 may enhance the MC response to natural ligation of this novel form of CD8.