Expression of the normal form of prion protein (PrP(C)) has been reported on a wide range cells including lymphocytes and antigen presenting cells, however the functional role of PrP(C) remains to be fully elucidated. Here we report the effect of reintroducing the PrP gene into splenocytes derived from prion knockout (PrP 0/0) mice and comparing their responses with splenocytes lacking a functional PrP gene. Reintroduction of the PrP gene was carried out by transfecting cells with pC1PrPEH, a plasmid expressing mouse PrP. Following transfection, T cells demonstrated an increased capacity to proliferate in response to ConA and PMA/ionomycin compared to T cells lacking the functional PrP gene. A bioassay used to determine IL-2 levels indicated that the reintroduction of the PrP gene might enhance IL-2 expression in response to ConA. Levels of IFN-gamma produced also showed an increase following transfection with PrP expressing plasmid. A comparison between splenocytes derived from PrP 0/0 and PrP +/+ also demonstrated some differences in cytokine production and proliferation. Together these results show PrP(C) has an impact on the normal T cell activation and proliferation in response to mitogens and also potentially antigen responsiveness.