The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion

The costimulatory receptor OX40 has recently been shown to be involved in p rimary CD4 responses to several defined Ags, However, to date there has bee n little information regarding the mechanism of action of OX40, such as whe ther it regulates T cell numbers, reactivity, or both, and whether it contr ibutes to induction of long-term T cell responses. With an agonist Ab to OX 40, and by tracking Ag-specific TCR transgenic T cells in vivo, we show tha t ligation of OX40 induces clonal expansion and survival of CD4 cells durin g primary responses, and results in the accumulation of greater numbers of memory cells with time. Significantly, OX40-deficient T cells, from mice ge nerated by gene targeting, secrete IL-2 and proliferate normally during the initial period of activation, but cannot sustain this during the latter ph ases of the primary response, exhibiting decreased survival over time. Mice lacking OX40 develop only low frequencies of Ag-specific CD4 cells late in primary responses in vivo and generate dramatically lower frequencies of s urviving memory cells. These results demonstrate that OX40-OX40L interactio ns control primary T cell expansion and the ability to retain high numbers of Ag-specific T cells. In this way, OX40 signals promote survival of great er numbers of T cells with time and control the size of the memory T cell p ool.