Inhibition of interleukin 2 signaling and signal transducer and activator of transcription (STAT)5 activation during T cell receptor-mediated feedback inhibition of T cell expansion.
Limitation of clonal expansion of activated T cells is necessary for immune homeostasis, and is achieved by growth arrest and apoptosis. Growth arrest and apoptosis can occur passively secondary to cytokine withdrawal, or can be actively induced by religation of the T cell receptor (TCR) in previously activated proliferating T cells. TCR-induced apoptosis appears to require prior growth arrest, and is mediated by death receptors such as Fas. We tested whether TCR religation affects T cell responses to interleukin (IL)-2, a major T cell growth and survival factor. TCR ligation in activated primary human T cells blocked IL-2 induction of signal transducer and activator of transcription (STAT)5 DNA binding, phosphorylation of STAT5, Janus kinase (Jak)1, Jak3, and Akt, and kinase activity of Jak1 and Jak3. Inhibition was mediated by the mitogen-activated protein kinase kinase (MEK)-extracellular stimulus-regulated kinase (ERK) signaling pathway, similar to the mechanism of inhibition of IL-6 signaling we have described previously. TCR ligation blocked IL-2 activation of genes and cell cycle regulatory proteins, and suppressed cell proliferation and expansion. These results identify TCR-induced inhibition of IL-2 signaling as a novel mechanism that underlies antigen-mediated feedback limitation of T cell expansion, and suggest that modulation of cytokine activity by antigen receptor signals plays an important role in the regulation of lymphocyte function.
Lee
I H
IH
Department of Medicine, Hospital for Special Surgery, New York, New York 10021, USA.
Li
W P
WP
Hisert
K B
KB
Ivashkiv
L B
LB
D000906:Antibodies / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D017930:Genes, Reporter; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000276:immunology; D008894:Milk Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology*; D015534:Trans-Activators / Q000276:immunology*; D014162:Transfection
D000906:Antibodies; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt