IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response

J Immunol. 2005 Aug 15;175(4):2261-9. doi: 10.4049/jimmunol.175.4.2261.

Abstract

IL-21, a newly described cytokine belonging to the IL-2 gamma-chain receptor cytokine family (that includes IL-2, IL-7, and IL-15), has been described as an important regulator of the cellular immune response. In this study, the role of IL-21 in the generation of a human Ag-specific CD8+ T cell response is characterized by tracking a rare, but measurable population of self-Ag-specific T cells in vitro. Autologous dendritic cells pulsed with the melanoma antigen recognized T cells 1 self-peptide were used to stimulate CD8+ T cells from HLA-A2+ healthy donors and melanoma patients. We demonstrate that exposure to IL-21 increased the total number of MART-1-specific CD8+ T cells that could be elicited by >20-fold and, at the clonal level, enriched for a population of high-affinity CD8+ T cells with a peptide dose requirement more than 1 log(10)-fold less than their untreated counterparts. Phenotypic analysis of T cells from IL-21-treated cultures revealed a unique population of CD45RO+ CD28(high) CD8+ T cells, a phenotype that was stable for at least 4 wk after IL-21 exposure. These CD28(high) CD8+ T cells produced IL-2 upon Ag stimulation and represent potential helper-independent CTLs. Our studies demonstrate a significant role for IL-21 in the primary Ag-specific human CTL response and support the use of IL-21 in the ex vivo generation of potent Ag-specific CTLs for adoptive therapy or as an adjuvant cytokine during in vivo immunization against tumor Ags.

Publication types

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

MeSH terms

  • Adjuvants, Immunologic / physiology*
  • CD28 Antigens / biosynthesis
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Adhesion / immunology
  • Cell Line
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Clone Cells
  • Cytotoxicity Tests, Immunologic* / methods
  • Epitopes, T-Lymphocyte / immunology*
  • Humans
  • Immunophenotyping* / methods
  • Interleukins / physiology*
  • Leukocyte Common Antigens / biosynthesis
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Melanoma / immunology
  • Melanoma / pathology
  • Receptors, CCR7
  • Receptors, Chemokine / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism

Substances

  • Adjuvants, Immunologic
  • CCR7 protein, human
  • CD28 Antigens
  • Epitopes, T-Lymphocyte
  • Interleukins
  • Receptors, CCR7
  • Receptors, Chemokine
  • Leukocyte Common Antigens
  • interleukin-21