International Immunology, Vol. 11, No. 12, 1971-1980,
December 1999
© 1999 Japanese Society for Immunology
Optimal activation of tumor-reactive T cells by selected antigenic peptide analogues
Division of Clinical Onco-immunology, Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, CHUV, 1011 Lausanne, Switzerland
1 Unit 463, Institut National de la Santé et de la Recherche Médicale, F-44035 Nantes, France
2 Institute of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland
3 Institute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK
Correspondence to: D. Valmori
Many mechanisms have been proposed to explain why immune responses against human tumor antigens are generally ineffective. For example, tumor cells have been shown to develop active immune evasion mechanisms. Another possibility is that tumor antigens are unable to optimally stimulate tumor-specific T cells. In this study we have used HLA-A2/Melan-A peptide tetramers to directly isolate antigen-specific CD8+ T cells from tumor-infiltrated lymph nodes. This allowed us to quantify the activation requirements of a representative polyclonal yet monospecific tumor-reactive T cell population. The results obtained from quantitative assays of intracellular Ca2+ mobilization, TCR down-regulation, cytokine production and induction of effector cell differentiation indicate that the naturally produced Melan-A peptides are weak agonists and are clearly suboptimal for T cell activation. In contrast, optimal T cell activation was obtained by stimulation with recently defined peptide analogues. These findings provide a molecular basis for the low immunogenicity of tumor cells and suggest that patient immunization with full agonist peptide analogues may be essential for stimulation and maintenance of anti-tumor T cell responses in vivo.
Keywords: cytotoxicity, cytotoxic T lymphocyte, T lymphocytes, tumor immunity, vaccination
The first two authors contributed equally to this work and the last two authors share senior authorship
Transmitting editor: P. C. L. Beverley
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