Suppression of early IL-4 production underlies the failure of CD4 T cells activated by TLR-stimulated dendritic cells to differentiate into Th2 cells.
Dendritic cells (DCs) activated through TLRs provide a potent negative signal for Th2 cell development that is independent of positive signals for Th1 cell development such as IL-12 and IFN-gamma. In this study we demonstrate that the ability of TLR-activated DCs to suppress Th2 cell development is Ag dose-independent and unique to DCs that have been activated through TLRs vs by cytokines. We show that TLR-activated DCs inhibit early IL-4 production by CD4 T cells and thus inhibit their ability to subsequently increase GATA-3 expression and commit to the Th2 lineage. This occurs independently of expression of the GATA-3 antagonist T-bet. Although CD4 T cells activated by TLR-activated DCs make IL-2, they are not capable of phosphorylating STAT5 in response to this cytokine. This inhibition of responsiveness to IL-2 appears to underlie the failure to make early IL-4. Our findings suggest that DCs provide instructional signals for T cell differentiation before cytokine-mediated Th cell selection and outgrowth.
Sun
Jie
J
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Pearce
Edward J
EJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D050990:GATA3 Transcription Factor / Q000235:genetics; D007376:Interleukin-2 / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D018418:Th2 Cells / Q000166:cytology*; D051193:Toll-Like Receptors / Q000502:physiology*; D015854:Up-Regulation
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007376:Interleukin-2; D051193:Toll-Like Receptors; D015847:Interleukin-4