T cell fitness determined by signal strength

Nat Immunol. 2003 Apr;4(4):355-60. doi: 10.1038/ni908. Epub 2003 Mar 17.


Two potential outcomes confront proliferating antigen-stimulated naive T cells: differentiation to effector and memory cells, or deletion. How stimulation affects cell fate is unclear. Autonomous CD8+ T cell differentiation has been proposed, but this does not explain the abortive proliferation of T cells induced by immature dendritic cells. Here we show that human and mouse CD4+ and CD8+ T cells receiving short or weak stimulation of the T cell receptor proliferate in response to interleukin 2 (IL-2) but are not 'fit' because they die by neglect, fail to proliferate in response to IL-7 and IL-15 and disappear in vivo. Conversely, prolonged or strong stimulation promotes 'fitness' by enhancing survival and cytokine responsiveness. Our results are consistent with the concept that signal strength drives progressive T cell differentiation and the acquisition of fitness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / physiology*
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Survival
  • Dendritic Cells / physiology
  • Humans
  • Interleukin-10 / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Cytokine / metabolism
  • bcl-X Protein


  • BCL2L1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, T-Cell
  • Receptors, Cytokine
  • bcl-X Protein
  • Interleukin-10