Differential modulation of CD4 and CD8 T-cell roliferation by induction of nitric oxide synthesis in anigen presenting cells1.

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Abstract
On antigenic stimulation, CD4 T cells generally proliferate more readily than CD8 T cells. The purpose of the present experiments was to determine whether nitric oxide (NO) might differentially modulate CD4 vs. CD8 T-cell proliferation. Various concentrations of C57BL/6 iNOS +/+ and -/- bone marrow (BM)-derived antigen presenting cells (APC) (obtained by culture in granulocyte-macrophage colony-stimulating factor [GM-CSF] and interleukin [IL]-4) were cultured with purified BALB/c CD4 or CD8 T cells. Proliferation of CD4 T cells was similar in the presence of both NO synthase (iNOS) +/+ and -/- APC, whereas CD8 T cell proliferation was inhibited at the higher concentrations of iNOS +/+ dendritic cells (DC), coincident with increased levels of NO in the culture supernatant. Analysis of cytokine levels revealed that more interferon (IFN)-gamma, a potent inducer of NO synthesis in many cell types, was present in CD8 T cell than in CD4 T-cell-APC cultures. Addition of IFN-gamma to CD4 T-cell-APC cultures resulted in induction of NO synthesis and inhibition of proliferation at higher levels of NO than that required to inhibit CD8 T cell proliferation. However, CD4 T-cell proliferation was moderately inhibited in the presence of lipopolysaccharide (LPS)-stimulated CD11c DC, coincident with production of IFN-gamma and induction of NO synthesis. These findings indicate that CD8 T-cell proliferation can be inhibited by lesser amounts of APC-derived NO than is necessary to inhibit CD4 T cell proliferation. NO synthesis was not initiated in CD4 T cell-DC cultures unless costimulatory molecules were up-regulated and IFN-gamma was produced.