T cell genetic background determines maintenance of IL-12 signaling: effects on BALB/c and B10.D2 T helper cell type 1 phenotype development.
In this report, we examined the molecular basis underlying the genetic difference between BALB/c and B10.D2 T cells for T helper phenotype development in vitro. We found a strain-dependent difference in early maintenance of IL-12 responsiveness by T cells developing in vitro in unmanipulated (neutral) conditions. Thus, when activated without addition of exogenous cytokines or neutralization of endogenous cytokines, B10.D2, but not BALB/c, T cells remain responsive to IL-12 when activated for 7 days. The pattern of IL-12 responsiveness correlated with expression of the IL-12R signaling subunit, IL-12R beta2, and with IL-12-induced STAT4 phosphorylation. When activated under neutral conditions, BALB/c T cells rapidly lose IL-12R beta2 expression, STAT4 phosphorylation, and functional IL-12 responsiveness. More efficient maintenance of IL-12R beta2 expression by B10.D2 T cells activated under neutral conditions may explain the previously observed increase in IFN-gamma production relative to that of BALB/c. This difference could potentially provide greater protection from certain pathogens that do not immediately elicit strong Th1-inducing conditions via activation of the innate immune system.
Güler
M L
ML
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jacobson
N G
NG
Gubler
U
U
Murphy
K M
KM
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000235:genetics; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D013045:Species Specificity; D018417:Th1 Cells / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; C508443:Il12rb2 protein, mouse; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D007371:Interferon-gamma