Loss of T Regulatory Cell Suppression following Signaling through Glucocorticoid-induced Tumor Necrosis Receptor (GITR) Is Dependent on c-Jun N-terminal Kinase Activation

Background: Ligation of the glucocorticoid-induced tumor necrosis (TNF) receptor (GITR) regulates T suppressor cell activity. Results: Regulation of JNK phosphorylation following GITR ligation plays a central role in the suppressive activity of T regulatory cells. Conclusion: Inhibition of JNK phosphorylation modulates T regulatory effector cell function in vitro and in vivo. Significance: Identification of JNK phosphorylation as a regulator of T suppressor cell function. Naturally occurring Foxp3 CD4 CD25 T regulatory cell (nTreg)-mediated suppression of lung allergic responses is abrogated following ligation of glucocorticoid-induced tumor necrosis receptor (GITR) family-related protein. In vitro stimulation of nTregs with GITR ligand increased phosphorylation of c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated protein kinase (ERK) or p38 MAPK. SP600125, a known JNK inhibitor, prevented GITR-mediated phosphorylation of JNK. Activation of JNK was associated with increases in the upstream mitogen-activated protein kinase kinase 7 (MKK7) and the downstream transcription factor NF-. Phosphorylated c-Jun (p-c-Jun), indicative of the activation of JNK, was detected in the immunoprecipitates of nTregs from wild-type but not JNK-or GITR-deficient mice. Treatment with an inhibitor of JNK phosphorylation resulted in complete reversal of all GITR-induced changes in nTreg phenotype and function, with full restoration of suppression of in vivo lung allergic responses and in vitro proliferation of activated CD4 CD25 T cells. Thus, regulation of JNK phosphorylation plays a central role in T regulatory cell function with therapeutic implications for the treatment of asthma and autoimmune diseases.