T cell fitness determined by signal strength.
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.
Gett
Amanda V
AV
Institute for Research in Biomedicine, Via Vela 6, CH-6500 Bellinzona, Switzerland.
Sallusto
Federica
F
Lanzavecchia
Antonio
A
Geginat
Jens
J
D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002470:Cell Survival; D003713:Dendritic Cells / Q000502:physiology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D018121:Receptors, Cytokine / Q000378:metabolism; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D018121:Receptors, Cytokine; D051020:bcl-X Protein; D016753:Interleukin-10