IL-2 Produced by CD8+ Immune T Cells Can Augment Their IFN-γ Production Independently from Their Proliferation in the Secondary Response to an Intracellular Pathogen

Chronic infection with Toxoplasma gondii induces a potent resistance against reinfection, and IFN-gamma production by CD8(+) T cells is crucial for the protective immunity. However, the molecular mechanisms that regulate the secondary response remain to be elucidated. In the current study, we examined the role of IL-2 in IFN-gamma production by CD8(+) immune T cells in their secondary responses using T. gondii-specific CD8(+) T cell hybridomas and splenic CD8(+) immune T cells from chronically infected mice. The majority (92%) of CD8(+) T cell hybridomas produced large amounts of IFN-gamma only when a low amount (0.5 ng/ml) of exogenous IL-2 was provided in combination with T. gondii Ags. Inhibition of cell proliferation by mitomycin C did not affect the enhancing effect of IL-2 on the IFN-gamma production, and significant increases in transcription factor T-bet expression were associated with the IL-2-mediated IFN-gamma amplification. Splenic CD8(+) immune T cells produced similar low levels of IL-2 in the secondary response to T. gondii, and a blocking of IL-2 signaling by anti-IL-2R alpha Ab or inhibitors of JAK1 and JAK3 significantly reduced IFN-gamma production of the T cells. This IL-2-mediated upregulation of IFN-gamma production was observed in mitomycin C-treated CD8(+) immune T cells, thus independent from their cell division. Therefore, endogenous IL-2 produced by CD8(+) immune T cells can play an important autocrine-enhancing role on their IFN-gamma production in the secondary responses to T. gondii, suggesting an importance of induction of CD8(+) immune T cells with an appropriate IL-2 production for vaccine development. The Journal of Immunology, 2013, 190: 2199-2207.