CD8(+) T cell tolerance to a tumor-associated antigen is maintained at the level of expansion rather than effector function

J Exp Med. 2002 Jun 3;195(11):1407-18. doi: 10.1084/jem.20011063.

Abstract

CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle to generating T cell responses to tumor-associated antigens. We have made a T cell receptor (TCR) transgenic mouse specific for a tumor antigen and crossed TCR-TG mice to transgenic mice expressing the tumor antigen in hepatocytes (gag-TG). TCRxgag mice showed no signs of autoimmunity despite persistence of high avidity transgenic CD8+ T cells in the periphery. Peripheral CD8+ T cells expressed phenotypic markers consistent with antigen encounter in vivo and had upregulated the antiapoptotic molecule Bcl-2. TCRxgag cells failed to proliferate in response to antigen but demonstrated cytolytic activity and the ability to produce interferon gamma. This split tolerance was accompanied by inhibition of Ca(2+) flux, ERK1/2, and Jun kinase phosphorylation, and a block in both interleukin 2 production and response to exogenous interleukin 2. The data suggest that proliferation and expression of specific effector functions characteristic of reactive cells are not necessarily linked in CD8+ T cell tolerance.

Publication types

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

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Calcium / metabolism
  • Cell Division
  • Cell Extracts
  • Flow Cytometry
  • Gene Expression
  • Immune Tolerance / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • Spleen / cytology
  • Spleen / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • fas Receptor / metabolism
  • ras Proteins / metabolism

Substances

  • Antigens, Neoplasm
  • Cell Extracts
  • Interleukin-2
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, T-Cell
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Interferon-gamma
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins
  • Calcium