Nuclear factor-κB1 controls the functional maturation of dendritic cells and prevents the activation of autoreactive T cells

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Abstract

Mature dendritic cells (DCs) are crucial for the induction of adaptive immune responses and perturbed DC homeostasis can result in autoimmune disease. Either uncontrolled expansion1 or enhanced survival2,3 of DCs can result in a variety of autoimmune diseases in mouse models. In addition, increased maturation signals, through overexpression of surface Toll-like receptors (TLRs)4 or stimulation by type I interferon (IFN)5, has been associated with systemic autoimmunity. Whereas recent studies have focused on identifying factors required for initiating the maturation process, the possibility that resting DCs also express molecules that 'hold' them in an immature state has generally not been considered. Here we show that nuclear factor–κB1 (NF-κB1) is crucial for maintaining the resting state of DCs. Self-antigen–pulsed unstimulated DCs that do not express NF-κB1 were able to activate CD8+ T lymphocytes and induce autoimmunity. We further show that NF-κB1 negatively regulates the spontaneous production of tumor necrosis factor-α (TNF-α), which is associated with increased granzyme B expression in cytotoxic T lymphocytes (CTLs). These findings provide a new perspective on functional DC maturation and a potential mechanism that may account for pathologic T cell activation.

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Figure 1: TLR-stimulated, antigen-pulsed DCs induce diabetes in RIP-gp mice.
Figure 2: NF-κB1–deficient DCs do not require TLR maturation to induce diabetes.
Figure 3: NF-κB1–deficient DCs do not upregulate makers of maturation but spontaneously produce TNF-α.
Figure 4: The induction of diabetes in RIP-gp mice is dependent upon TNF-α production by transferred DCs.

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Acknowledgements

We would like to thank S. Mariathasan (Genentech) for kindly providing Pycard-deficient mice. We would also like to thank L.T. Nguyen for critical evaluation of the manuscript. This work was supported by a Canadian Institutes for Health Research (CIHR) grant to P.S.O. and CIHR studentship to D.D. P.S.O. holds a Canada Research Chair in Autoimmunity and Tumor Immunity. This research was funded in part by the Ontario Ministry of Health and Long Term Care (OMHLTC). The views expressed do not necessarily reflect those of the OMHLTC.

Author information

D.D. and P.S.O. designed and supervised the project, analyzed the data and wrote the manuscript. H.H., A.R.E., S.R.H. and K.M. assisted with experiments. N.B.-B., L.S.D. and J.L.G. performed supporting experiments.

Correspondence to Pamela S Ohashi.

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The authors declare no competing financial interests.

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