CD28, TNF receptor, and IL-12 are critical for CD4-independent cross-priming of therapeutic antitumor CD8+ T cells.
Previously, we have shown that priming of therapeutic CD8(+) T cells in tumor vaccine-draining lymph nodes of mice vaccinated with GM-CSF secreting B16BL6 melanoma cells occurs independent of CD4 T cell help. In this study, we examined the contribution of the major costimulatory molecules, CD40 ligand (CD40L), CD80, and CD86, in the priming of CD8(+) T cells. Priming of therapeutic CD8(+) T cells by a GM-CSF-transduced tumor vaccine did not require CD40 and CD40L interactions, as therapeutic T cells could be generated from mice injected with anti-CD40L Ab and from CD40L knockout mice. However, costimulation via either CD80 or CD86 was required, as therapeutic T cells could be generated from mice injected with either anti-CD80 or anti-CD86 Ab alone, but administration of both Abs completely inhibited the priming of therapeutic T cells. Blocking experiments also identified that priming of therapeutic T cells in MHC class II-deficient mice required TNFR and IL-12 signaling, but signaling through CD40, lymphotoxin-betaR, or receptor activator of NF-kappaB was not essential. Thus, cross-priming of therapeutic CD8(+) T cells by a tumor vaccine transduced with GM-CSF requires TNFR, IL-12, and CD28 signaling.
Hu
Hong-Ming
HM
Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center and Providence Portland Medical Center, OR 97213, USA.
Winter
Hauke
H
Ma
Jun
J
Croft
Michael
M
Urba
Walter J
WJ
Fox
Bernard A
BA
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D018122:B7-1 Antigen / Q000502:physiology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology*; D015704:CD4 Antigens / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods; D018664:Interleukin-12 / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D015704:CD4 Antigens; D019013:CD40 Antigens; D019496:Cancer Vaccines; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12