Reduced antigen concentration and costimulatory blockade increase IFN-gamma secretion in naive CD8+ T cells.

CD8+ T cells are killer cells but also major producers of IFN-gamma. We have investigated the effects of peptide antigen titration and costimulatory blockade on IFN-gamma production and proliferation by naive CD8+ T cells. Mature dendritic cells (DC) pulsed with high amounts of agonist peptide triggered proliferation but little IFN-gamma secretion in individual T cells. In contrast, immature DC pulsed with similar amounts of peptide induced IFN-gamma secretion in a larger fraction of T cells but triggered less proliferation. Blocking B7.2 or lowering the amount of peptide on mature DC led to a response similar to that induced by immature DC, suggesting that differences in stimulatory strength were responsible for the different responses. Using splenic antigen-presenting cells (APC) we demonstrate that reducing the amount of peptide in combination with B7 blockage enhanced IFN-gamma secretion and decreased proliferation in naive CD8+ T cells in an additive way. Our data suggest that IFN-gamma secretion and proliferation are independently and inversely controlled by stimulatory strength in naive CD8+ T cells. This may enable CD8+ T cells to respond with IFN-gamma secretion to immature APC with few peptide ligands consistent with an early immunoregulatory role of CD8+ T cells.