The protective effect of primed CD4 T cells against a lethal dose of Salmonella typhimurium was studied in Lewis rats. Primed CD4 T cells were obtained by inoculating Lewis rats with a non-lethal dose of S. typhimurium. Four weeks after the infection, spleen non-adherent mononuclear cells were isolated. The cells were separated according to their expression of CD4 and the OX40 antigen by FACS. OX40+ and OX40- CD4+ T-cell subpopulations were together with unsorted CD4+ T cells transferred to untreated rats 24 h prior to infection with S. typhimurium. Transfer of either unsorted CD4+ T cells or CD4+ T cells sorted into OX40- or OX40- subpopulations significantly increased animal survival compared to controls. Animals receiving OX40+CD4+ T cells did not differ significantly in survival probability from those receiving unsorted CD+ T cells. However, animals receiving OX40-CD4+ T cells had a significantly better survival compared to animals given unsorted CD4+ T cells. It is concluded that OX40-CD4+ T cells can induce significant protection against S. typhimurium infections in rats. This is most likely due to the fact that the OX40-CD4+ T-cell population contains a significant number of antigen-specific memory T cells that have returned to a resting state.