Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors

Nat Med. 2006 Mar;12(3):335-41. doi: 10.1038/nm1359. Epub 2006 Feb 12.


CD8+ T cells can mediate eradication of established tumors, and strategies to amplify tumor-reactive T-cell numbers by immunization or ex vivo expansion followed by adoptive transfer are currently being explored in individuals with cancer. Generating effective CD8+ T cell-mediated responses to tumors is often impeded by T-cell tolerance to relevant tumor antigens, as most of these antigens are also expressed in normal tissues. We examined whether such tolerant T cells could be rescued and functionally restored for use in therapy of established tumors. We used a transgenic T-cell receptor (TCR) mouse model in which peripheral CD8+ T cells specific for a candidate tumor antigen also expressed in liver are tolerant, failing to proliferate or secrete interleukin (IL)-2 in response to antigen. Molecular and cellular analysis showed that these tolerant T cells expressed the IL-15 receptor alpha chain, and could be induced to proliferate in vitro in response to exogenous IL-15. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia. Therefore, high-affinity CD8+ T cells are not necessarily deleted by encounter with self-antigen in the periphery, and can potentially be rescued and expanded for use in tumor immunotherapy.

Publication types

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

MeSH terms

  • Animals
  • CD8 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Fas Ligand Protein
  • Humans
  • Immune Tolerance / immunology*
  • Immunologic Memory / immunology
  • Immunotherapy, Adoptive*
  • Interleukin-15 / pharmacology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / therapy*
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2 / metabolism
  • Tumor Necrosis Factors / metabolism


  • CD8 Antigens
  • FASLG protein, human
  • Fas Ligand Protein
  • Fasl protein, mouse
  • IL15RA protein, human
  • Il15ra protein, mouse
  • Interleukin-15
  • Membrane Glycoproteins
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2
  • Tumor Necrosis Factors

Associated data

  • GEO/GSE3800