OX40 costimulatory signals potentiate the memory commitment of effector CD8⁺ T cells

A T cell costimulatory molecule, OX40, contributes to T cell expansion, survival, and cytokine production. Although several roles for OX40 in CD8 ⁺ T cell responses to tumors and viral infection have been shown, the precise function of these signals in the generation of memory CD8⁺ T cells remains to be elucidated. To address this, we examined the generation and maintenance of memory CD8⁺ T cells during infection with Listeria monocytogenes in the presence and absence of OX40 signaling. We used the expression of killer cell lectin-like receptor G1 (KLRG1), a recently reported marker, to distinguish between short-lived effector and memory precursor effector T cells (MPECs). Although OX40 was dispensable for the generation of effector T cells in general, the lack of OX40 signals significantly reduced the number and proportion of KLRG1^low MPECs, and, subsequently, markedly impaired the generation of memory CD8⁺ T cells. Moreover, memory T cells that were generated in the absence of OX40 signals in a host animal did not show self-renewal in a second host, suggesting that OX40 is important for the maintenance of memory T cells. Additional experiments making use of an inhibitory mAb against the OX40 ligand demonstrated that OX40 signals are essential during priming, not only for the survival of KLRG1^low MPECs, but also for their self-renewing ability, both of which contribute to the homeostasis of memory CD8⁺ T cells.