CD4(+) T cells are critical for the control of many viruses; however, the numbers of virus-specific CD4(+) cells that are expanded following infection are unknown. We have addressed this issue by enumerating virus-specific, MHC class-II-restricted T cells following infection of mice with lymphocytic choriomeningitis virus (LCMV). We have found that the numbers of T cells that produce interferon-gamma in response to stimulation with three different class-II-restricted LCMV epitopes increase from undetectable numbers in noninfected animals to between 4 x 10(5) and 2 x 10(6) cells per spleen at the peak of the T cell response. This contrasts with the numbers of virus-specific class-restricted T cells which expand ttl 1 x 10(7) to 2 x 10(7) cells per spleen during the same time period. We could not reproducibly detect virus-specific class-I-restricted or class-II-restricted T cells that produced interleukin-4 at any time following LCMV infection, indicating that infection with this virus induces a predominantly type 1 cytokine response. In contrast to the rapid decrease in the numbers of class-I-restricted T cells, the numbers of LCMV-specific class-II-restricted T cells declined gradually following the peak of the T cell response. We demonstrate, therefore, that following infection with LCMV there is expansion of both class-I-restricted and class-II-restricted virus-specific T cells; however, the degree of expansion of class-II-restricted T cells is substantially less than that observed for class-I-restricted cells. Furthermore, the downregulation phase of the class-II-restricted response is protracted compared with the precipitous contraction of the antiviral CD8(+) T cell response. (C) 1999 Academic Press.