Addition of concanavalin A (Con A) to a culture of spleen cells of ODS-od/od rats, which cannot synthesize ascorbic acid, increased the activity of histidine decarboxylase (HDC) in the culture, leading to accumulation of histamine (Hm) in the medium. Treatment of the culture with cimetidine, a type 2 Hm antagonist, enhanced Con A-dependent lymphocyte blastogenesis even in the absence of any exogenously added Hm. Addition of low doses of histaminase increased Con A-dependent lymphocyte transformation. At higher doses, it abrogated the reaction. At concentrations of more than 10(-10) M, exogenously added Hm suppressed the Con A-dependent uptake of [3H]thymidine by the lymphocytes, but it significantly augmented the response at 10(-14) M. The addition of ascorbic acid (10(-8)-10(-5) M) to the culture suppressed the Con A-mediated HDC induction and inhibited Hm biosynthesis. Concomitantly added ascorbic acid at the concentrations of 10(-8)-10(-4) M increased the uptake of [3H]thymidine dependent on Con A or phytohemagglutinin by the lymphocytes. These results suggest that mitogen-dependent lymphocyte blastogenesis is activated by Hm produced by the spleen cells per se. However, when culture was prolonged, high concentrations of Hm suppressed the reaction. Ascorbic acid enhances mitogen-dependent lymphocyte blastogenesis through inhibition of HDC induction, leading to attenuation of immunosuppressive Hm production by the spleen cells.