Engagement of OX40 Enhances Antigen-Specific CD4+ T Cell Mobilization/Memory Development and Humoral Immunity: Comparison of αOX-40 with αCTLA-4

Abstract

Increasing the long-term survival of memory T cells after immunization is key 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 are susceptible to activation-induced cell death. Previously, we reported that OX40 engagement resulted in a 60-fold increase in the number of Ag-specific CD4+ memory T cells that persisted 60 days postimmunization. In this report, 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 αOX40, and the Ag-specific Ab response after immunization with soluble OVA and αOX40. Finally, we compared the adjuvant properties of αOX40 to those of αCTLA-4. Engagement of OX-40 in vivo was most effective when the Ag was administered s.c. Time course studies revealed that it was crucial for αOX40 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 αOX40 compared with mice that received OVA alone. Both αOX40 and αCTLA-4 increased the percentage of OVA-specific CD4+ T cells early after immunization (day 4), but αOX40-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 humoral immunity in a manner distinct from that provided by blocking CTLA-4.

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

“…There is therefore a lag phase during which T cells are recruited and Ag activated before OX40L:Ig can exert its effect. Enhanced T cell responses by OX40 engagement have also been reported in TCR transgenic mice in which responsiveness to Ag persisted 95 days after initial Ag exposure (47) and in vitro using OX40L-transfected fibroblasts (5,8).…”

“…Although we did not observe a change in intracellular IL-5 expression by CD4 ϩ T cells, the cytokine balance is definitely in favor of a Th1 environment in wild-type mice following OX40L:Ig treatment. The induction of IFN-␥ by enhanced OX40 signaling has been described previously in recall responses to Ags (47,52). CD8 ϩ intraepithelial lymphocytes expressing OX40 and OX40L after CD3 stimulation also produce high levels of IFN-␥ (53).…”

Intracellular Signals of T Cell Costimulation

“…OX40 engagement can boost the generation of antigenspecific T cell memory (84,85), particularly control memory T helper 2 cells that drive lung inflammation (86,87). The molecular targets of OX40 that regulate memory development is still unclear, but OX40 sustains expression of bcl-xL, which controls long-term T cell survival, suggesting that bcl-xL might also mediate memory T cell development (76).…”

Targeting macrophages in the tumour environment to enhance the efficacy of αOX40 therapy

“…OX40 is transiently up-regulated following antigen receptor signalling on CD4 and Michael J. Gough, 1 N. Killeen, 2 Andrew D. Weinberg 1 1 CD8 T cells, and ligation of OX40 by antibodies or its natural ligand (OX40L/CD252) results in improved expansion, effector function and long-term survival of CD4 and CD8 T cells. [12][13][14][15][16] Expression of the ligand for OX40 is tightly associated with acute inflammation, and has been demonstrated at sites of psoriasis, 17 rheumatoid arthritis 18 and autoimmune demyelination. 19 Provision of agonistic antibodies to OX40 (aOX40) significantly enhances antigen-specific T-cell responses to soluble antigen 12,14 and to antigens expressed in cancer cell lines.…”

“…[12][13][14][15][16] Expression of the ligand for OX40 is tightly associated with acute inflammation, and has been demonstrated at sites of psoriasis, 17 rheumatoid arthritis 18 and autoimmune demyelination. 19 Provision of agonistic antibodies to OX40 (aOX40) significantly enhances antigen-specific T-cell responses to soluble antigen 12,14 and to antigens expressed in cancer cell lines. 13 This suggests that the lack of OX40 signalling may be a limiting factor to generate optimal antigen-specific immune responses in vivo.…”