LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells

Abstract

Liver Kinase B1 (LKB1) plays a key role in cellular metabolism by controlling AMPK activation. However, its function in dendritic cell (DC) biology has not been addressed. Here, we find that LKB1 functions as a critical brake on DC immunogenicity, and when lost, leads to reduced mitochondrial fitness and increased maturation, migration, and T cell priming of peripheral DCs. Concurrently, loss of LKB1 in DCs enhances their capacity to promote output of regulatory T cells (Tregs) from the thymus, which dominates the outcome of peripheral immune responses, as suggested by increased resistance to asthma and higher susceptibility to cancer in CD11cΔLKB1 mice. Mechanistically, we find that loss of LKB1 specifically primes thymic CD11b+ DCs to facilitate thymic Treg development and expansion, which is independent from AMPK signalling, but dependent on mTOR and enhanced phospholipase C β1-driven CD86 expression. Together, our results identify LKB1 as a critical regulator of DC-driven effector T cell and Treg responses both in the periphery and the thymus.

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Acknowledgements

This work was supported by an LUMC and Marie Curie fellowship awarded to B.E.

Author information

B.E., L.R.P., T.A.P., A.J.v.d.H., F.O., H.v.d.Z., S.v.d.S., A.S., A.O.-F. and E.E. performed experiments; B.E., M.N.A., L.R.P., A.S. and E.E. designed and analyzed experiments; B.E. conceived and supervised the study and wrote the manuscript together with L.R.P.

Correspondence to Bart Everts.

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Pelgrom, L.R., Patente, T.A., Sergushichev, A. et al. LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells. Cell Res 29, 406–419 (2019) doi:10.1038/s41422-019-0161-8

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