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

J Immunother. May-Jun 2005;28(3):220-8. doi: 10.1097/01.cji.0000156828.75196.0d.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Antigens, Neoplasm / immunology*
  • B-Cell Lymphoma 3 Protein
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / immunology*
  • Dendritic Cells / immunology
  • Dendritic Cells / transplantation*
  • Immunologic Memory / drug effects
  • Membrane Glycoproteins / agonists*
  • Mice
  • Mice, Transgenic
  • Neoplasms, Experimental / immunology*
  • Peptides / immunology
  • Poly I-C / pharmacology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Receptors, Cell Surface / agonists*
  • Signal Transduction
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Transcription Factors
  • Transcription, Genetic / drug effects
  • Vaccination / methods
  • bcl-X Protein

Substances

  • Adjuvants, Immunologic
  • Antigens, Neoplasm
  • B-Cell Lymphoma 3 Protein
  • Bcl2l1 protein, mouse
  • Bcl3 protein, mouse
  • Cancer Vaccines
  • Membrane Glycoproteins
  • Peptides
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Cell Surface
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Transcription Factors
  • bcl-X Protein
  • Poly I-C