Abstract
Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draining lymph node in a neuroinflammatory autoimmunity model, experimental autoimmune encephalomyelitis (EAE). At older ages, the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype. TBK1 controls the activation of AKT and its downstream kinase mTORC1 by a mechanism involving TBK1-stimulated AKT ubiquitination and degradation. The deregulated AKT-mTORC1 signalling in turn contributes to enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. Treatment of mice with a small-molecule inhibitor of TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis.
Highlights
Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues
To assess the function of TBK1 in T cells, we examined its ability to respond to signals stimulated by the TCR and CD28 agonistic antibodies or mitogens (PMA and ionomycin) that activate protein kinase C and calcium pathways downstream of the TCR and CD28
Similar results were obtained using Jurkat T cells lacking CARMA1 (JPM50.6) or NEMO (JM4.5.2; ref. 18; Fig. 1c). Both TBK1 and IKKe are activated by T-cell-activation signals, the underlying mechanism appeared to be different for these kinases
Summary
Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Treatment of mice with a small-molecule inhibitor of TBK1 inhibits EAE induction These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis. Following priming by the self-antigens in peripheral lymphoid organs, autoimmune effector T cells migrate to target organs to mediate inflammation and tissue damage. The signalling mechanism that regulates T-cell migration from the lymphoid organs to the tissues of autoimmunity, such as CNS, is still poorly defined. The T-cellconditional Tbk1-KO (hereafter called Tbk1-TKO) mice were refractory to the induction of EAE due to impaired migration of autoimmune T cells from the draining lymph nodes to the CNS. Our data suggest that TBK1 mediates egress of effector T cells from draining lymph nodes in a mechanism that involves negative regulation of the kinases AKT and mTORC1
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