Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38 alpha activation.
In anergic T cells, T-cell receptor (TCR)-mediated responses are functionally inactivated by negative regulatory signals whose mechanisms are poorly understood. Here, we show that CD4(+) T cells anergized in vivo by superantigen Mls-1(a) express a scaffolding protein, transforming growth factor beta-activated protein kinase 1-binding protein 1 (TAB1), that negatively regulates TCR signaling through the activation of mitogen-activated protein kinase p38 alpha. TAB1 was not expressed in naive and activated CD4(+) T cells. Inhibition of p38 activity in anergic T cells by a chemical inhibitor resulted in the recovery of interleukin 2 (IL-2) and the inhibition of IL-10 secretion. T-cell hybridoma 2B4 cells transduced with TAB1-containing retrovirus (TAB1-2B4 cells) showed activated p38 alpha, inhibited extracellular signal-regulated kinase (ERK) activity, culminating in reduced IL-2 levels and increased IL-10 production. The use of a p38 inhibitor or cotransfection of a dominant-negative form of p38 in TAB1-2B4 cells resulted in the recovery of ERK activity and IL-2 production. These results imply that TAB1-mediated activation of p38 alpha in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.
Division of Immunology, Department of Translational Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto, Nagasaki, Japan.
Kozo
K
Ohkusu-Tsukada
Norio
N
Tominaga
Heiichiro
H
Udono
Katsuyuki
K
Yui
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D017635:Clonal Anergy; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016747:Minor Lymphocyte Stimulatory Antigens / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D016747:Minor Lymphocyte Stimulatory Antigens; D011948:Receptors, Antigen, T-Cell; C099510:TAB1 protein, MAPKKK activator, vertebrate; C486300:TAB1 protein, human; D016753:Interleukin-10; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases