Activation of MAP kinase p38 is critical for the cell-cycle-controlled suppressor function of regulatory T cells.
Regulatory T cells play an essential role in the control of self-tolerance and processes of adaptive immunity. Tolerogenic IL-10-modulated human dendritic cells (IL-10DCs) induce anergic T cells with strong suppressive properties (iTregs) that inhibit the activation of effector T cells. In this study, we evaluated the interaction between cell-cycle regulation and intracellular signaling in these iTregs. Analysis of signal transduction events revealed a down-regulation of the mitogen-activated protein kinases (MAPKs) Jun N-terminal kinase (JNK) and a nonactivation of extracellular-signal-regulated kinase (ERK) in contrast to a marked activation of p38 MAPK and the p38 effector MAPK-activated protein kinases 2/3 (MAPKAP2/3). The elevated activation of p38 is critical for the induction and maintenance of anergy controlled by an increased expression of the cell-cycle inhibitor p27(Kip1). Moreover, blocking experiments with the specific inhibitor SB203580 demonstrated that the regulatory function of iTregs is associated with an enhanced p38 MAPK activity. In contrast to other Treg populations, the suppressor function of iTregs is independent of IL-10. In conclusion, our data indicate that a cross-talk of cell-cycle regulation and p38-dependent signal transduction is required for the suppressor function of iTregs.
Adler
Henric S
HS
Department of Dermatology, University of Mainz, Mainz, Germany.
Kubsch
Sebastian
S
Graulich
Edith
E
Ludwig
Stephan
S
Knop
Juergen
J
Steinbrink
Kerstin
K
D002453:Cell Cycle; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology*; D000099190:MAP-Kinase-Activated Kinase 2
D050760:Cyclin-Dependent Kinase Inhibitor p27; D016753:Interleukin-10; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C508609:IL10 protein, human; C098416:MAP-kinase-activated kinase 3