Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: comparison of alphaOX-40 with alphaCTLA-4.
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 alphaOX40, and the Ag-specific Ab response after immunization with soluble OVA and alphaOX40. Finally, we compared the adjuvant properties of alphaOX40 to those of alphaCTLA-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 alphaOX40 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 alphaOX40 compared with mice that received OVA alone. Both alphaOX40 and alphaCTLA-4 increased the percentage of OVA-specific CD4(+) T cells early after immunization (day 4), but alphaOX40-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.
Evans
D E
DE
Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213, USA.
Prell
R A
RA
Thalhofer
C J
CJ
Hurwitz
A A
AA
Weinberg
A D
AD
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D001769:Blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D060908:CTLA-4 Antigen; D002465:Cell Movement; D002470:Cell Survival; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007156:Immunologic Memory; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000906:Antibodies; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007074:Immunoglobulin G; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000069594:Abatacept; D010047:Ovalbumin