title: In vivo ligation of CD40 enhances priming against the endogenous tumor antigen and promotes CD8+ T cell effector function in SV40 T antigen transgenic mice.
abstract: The ability to initiate and sustain CD8(+) T cell responses to tumors in vivo is hindered by the development of peripheral T cell tolerance against tumor-associated Ags. Approaches that counter the onset of T cell tolerance may preserve a pool of potentially tumor-reactive CD8(+) T cells. Administration of agonist Ab to the CD40 molecule, expressed on APCs, can enhance immunization approaches targeting T lymphocytes in an otherwise tolerance-prone environment. In this report, the effects of anti-CD40 administration on priming of naive CD8(+) T cells against an endogenous tumor Ag were investigated. Line 501 mice express the SV40 large T Ag oncoprotein as a transgene from the alpha-amylase promoter, resulting in the development of peripheral CD8(+) T cell tolerance to the H-2-D(b)-restricted immunodominant epitope I of T Ag by 6 mo of age, before the appearance of osteosarcomas. We demonstrate that naive epitope I-specific TCR transgenic (TCR-I) T cells undergo peripheral tolerance following adoptive transfer into 6-mo-old 501 mice. In contrast, administration of agonistic anti-CD40 Ab led to increased expansion of TCR-I T cells in 501 mice, the acquisition of effector function by TCR-I T cells and the establishment of T cell memory. Importantly, this enhanced priming effect of anti-CD40 administration did not require immunization and was effective even if administered after naive TCR-I T cells had encountered the endogenous T Ag. Thus, anti-CD40 administration can block the onset of peripheral tolerance and enhance the recruitment of functionally competent effector T cells toward an endogenous tumor Ag.
authors.affiliation: Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Staveley-O'Carroll
authors.forename: Todd D
authors.initials: TD
authors.lastname: Schell
authors.forename: Marcela
authors.initials: M
authors.lastname: Jimenez
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Mylin
authors.forename: M Judith
authors.initials: MJ
authors.lastname: Tevethia
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schoenberger
authors.forename: Satvir S
authors.initials: SS
authors.lastname: Tevethia
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics* / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002461:Cell Line, Transformed; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009333:Neck; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013539:Simian virus 40 / Q000235:genetics* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000957:Antigens, Viral, Tumor; D019013:CD40 Antigens; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D016693:Receptors, Antigen, T-Cell, alpha-beta; D023201:CD40 Ligand