Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: Comparison of alpha OX-40 with alphaCTLA-4

Increasing the long-term survival of memory T cells after immunization is k ey to a successful vaccine. In the past, the generation of large numbers of memory T cells in vivo has been difficult because Ag-stimulated T cells ar e susceptible to activation-induced cell death. Previously, we reported tha t OX40 engagement resulted in a 60-fold increase in the number of Ag-specif ic CD4(+) memory T cells that persisted 60 days postimmunization. In this r eport, we used the D011.10 adoptive transfer model to examine the kinetics of Ag-specific T cell entry into the peripheral blood, the optimal route of administration of Ag and alpha OX40, and the Ag-specific Ab response after immunization with soluble OVA and alpha OX40. Finally, we compared the adj uvant properties of alpha OX40 to those of alpha CTLA-4. Engagement of OX-4 0 in vivo was most effective when the Ag was administered s.c. Time course studies revealed that it was crucial for alpha OX40 to be delivered within 24-48 h after Ag exposure. Examination of anti-OVA Ab titers revealed a 10- fold increase in mice that received alpha OX40 compared with mice that rece ived OVA alone. Both alpha OX40 and alpha CTLA-4 increased the percentage o f OVA-specific CD4(+) T cells early after immunization (day 4), but alpha O X40-treated mice had much higher percentages of OVA-specific memory CD4(+) T cells from days 11 to 29. These studies demonstrate that OX40 engagement early after immunization with soluble Ag enhances long-term T cell and humo ral immunity in a manner distinct from that provided by blocking CTLA-4.