Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity.
Poly(I:C), a synthetic double-stranded RNA polymer and a TLR3 agonist, can be used as a vaccine adjuvant to enhance adaptive immunity. However, the antigen-specific CD8 T-cell response to peptide vaccination and poly(I:C) has not been clearly defined. Here, the authors characterized the antigen-specific CD8 T-cell response to peptide vaccination and poly(I:C) and specifically addressed the hypothesis that poly(I:C) can enhance antitumor immunity. To define the antigen-specific T-cell response, the authors established a model based on the adoptive transfer of T cells from the OT-1 T-cell receptor transgenic mouse. In this model, vaccination with peptide alone resulted in a limited, transient expansion of antigen-specific CD8 T cells. In contrast, peptide vaccination with concomitant administration of poly(I:C) resulted in a dramatic sustained increase in the number of antigen-specific CD8 T cells. This increase in cell number was associated with an increase in CD8 T-cell function, as defined by specific IFN-gamma and TNF-alpha production, and protection from tumor challenge. The adjuvant effects of poly(I:C) appear to be at least partially dependent on an increase in the transcription of the anti-apoptotic molecules Bcl-3 and Bcl-xL and a concomitant decrease in apoptosis during the contraction phase of the primary T-cell response. In addition, administration of poly(I:C) enhanced the response to a nonimmunogenic self-antigen in a dendritic cell vaccine-based vaccine strategy. Collectively, these results confirm the potential of poly(I:C) as a vaccine adjuvant and suggest that targeting of TLR3 is likely to be a valuable addition to peptide-based vaccination strategies.
Salem
Mohamed L
ML
Department of Surgery, Section of Surgical Oncology, Medical University of South Carolina, Charleston, South Carolina 29425, USA. salemm@musc.edu
Kadima
Andre N
AN
Cole
David J
DJ
Gillanders
William E
WE
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D000081242:B-Cell Lymphoma 3 Protein; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D007156:Immunologic Memory / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000819:agonists*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014611:Vaccination / Q000379:methods; D051020:bcl-X Protein
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D000081242:B-Cell Lymphoma 3 Protein; C494812:Bcl2l1 protein, mouse; C000631345:Bcl3 protein, mouse; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors; D051020:bcl-X Protein; D011070:Poly I-C