The effect of TGF-beta1 on immune responses of naïve versus memory CD4+ Th1/Th2 T cells.
The role of TGF-beta1 in the regulation of T cell responses has been perplexing, possibly because it is dependent on the type of T cell being regulated and its cytokine microenvironment. In the present study, we demonstrate that TGF-beta1 has a profound inhibitory effect on naive CD4+ T cell undergoing differentiation under defined neutral, Th1 and Th2 priming conditions. In addition, we show that if CD4+ T cells are primed in the presence of TGF-beta1, they exhibit reduced secondary anti-CD3/anti-CD28-induced and antigen-specific immune responses (even when TGF-beta is absent during the secondary response), which is not due to reduced expression of co-stimulatory molecules or to inadequate IL-2 production. Finally, with respect to the effect of TGF-beta on fully differentiated antigen-specific memory CD4+ T cells, we demonstrate that while antigen-specific activation and cytokine secretion by memory Th1 T cells is inhibited by TGF-beta1, such inhibition is associated with partial down-regulation of IL-12 receptor beta2 chain expression. In contrast, memory Th2 T cells are not subject to TGF-beta1 -mediated suppression. In summary, these studies reveal that TGF-beta1 is a powerful negative regulator of the primary immune response of CD4+ T cells, but only Th1 T cells are subject to such regulation after the memory stage of T cell differentiation has been reached. Thus, these studies define the potential regulatory role of TGF-beta1 in Th1 and Th2 T cell-mediated autoimmunity.
Lúdvíksson
B R
BR
Mucosal Immunity Section, LCI, NIAID, NIH, Bethesda 20892-1890, USA.
Seegers
D
D
Resnick
A S
AS
Strober
W
W
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000378:metabolism; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology*
D004268:DNA-Binding Proteins; C508440:Il12rb1 protein, mouse; C508443:Il12rb2 protein, mouse; D007376:Interleukin-2; C111390:OVA 323-339; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin