Cbl-b regulates antigen-induced TCR down-regulation and IFN-gamma production by effector CD8 T cells without affecting functional avidity

J Immunol. 2007 Dec 1;179(11):7233-43. doi: 10.4049/jimmunol.179.11.7233.


The E3 ubiquitin ligase Cbl-b is a negative regulator of TCR signaling that: 1) sets the activation threshold for T cells; 2) is induced in anergic T cells; and 3) protects against autoimmunity. However, the role of Cbl-b in regulating CD8 T cell activation and functions during physiological T cell responses has not been systematically examined. Using the lymphocytic choriomeningitis virus infection model, we show that Cbl-b deficiency did not significantly affect the clonal expansion of virus-specific CD8 T cells. However, Cbl-b deficiency not only increased the steady-state cell surface expression levels of TCR and CD8 but also reduced Ag-induced down-modulation of cell surface TCR expression by effector CD8 T cells. Diminished Ag-stimulated TCR down-modulation and sustained Ag receptor signaling induced by Cbl-b deficiency markedly augmented IFN-gamma production, which is known to require substantial TCR occupancy. By contrast, Cbl-b deficiency minimally affected cell-mediated cytotoxicity, which requires limited engagement of TCRs. Surprisingly, despite elevated expression of CD8 and reduced Ag-induced TCR down-modulation, the functional avidity of Cbl-b-deficient effector CD8 T cells was comparable to that of wild-type effectors. Collectively, these data not only show that Cbl-b-imposed constraint on TCR signaling has differential effects on various facets of CD8 T cell response but also suggest that Cbl-b might mitigate tissue injury induced by the overproduction of IFN-gamma by CD8 T cells. These findings have implications in the development of therapies to bolster CD8 T cell function during viral infections or suppress T cell-mediated immunopathology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Antigen Presentation / immunology
  • Antigens, Viral / immunology*
  • CD8 Antigens / biosynthesis
  • CD8 Antigens / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / virology
  • Disease Models, Animal
  • Down-Regulation / immunology
  • Epitopes, T-Lymphocyte / immunology
  • Interferon-gamma / biosynthesis*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Peptides / pharmacology
  • Proto-Oncogene Proteins c-cbl / biosynthesis
  • Proto-Oncogene Proteins c-cbl / deficiency
  • Proto-Oncogene Proteins c-cbl / physiology*
  • Receptors, Antigen, T-Cell / biosynthesis
  • Receptors, Antigen, T-Cell / metabolism*
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / immunology


  • Adaptor Proteins, Signal Transducing
  • Antigens, Viral
  • CD8 Antigens
  • Cblb protein, mouse
  • Epitopes, T-Lymphocyte
  • Peptides
  • Receptors, Antigen, T-Cell
  • Interferon-gamma
  • Proto-Oncogene Proteins c-cbl