Abstract
The serine/threonine kinase LKB1 has a conserved role in Drosophila and nematodes to co-ordinate cell metabolism. During T lymphocyte development in the thymus, progenitors need to synchronize increased metabolism with the onset of proliferation and differentiation to ensure that they can meet the energy requirements for development. The present study explores the role of LKB1 in this process and shows that loss of LKB1 prevents thymocyte differentiation and the production of peripheral T lymphocytes. We find that LKB1 is required for several key metabolic processes in T-cell progenitors. For example, LKB1 controls expression of CD98, a key subunit of the l-system aa transporter and is also required for the pre-TCR to induce and sustain the regulated phosphorylation of the ribosomal S6 subunit, a key regulator of protein synthesis. In the absence of LKB1 TCR-β-selected thymocytes failed to proliferate and did not survive. LBK1 was also required for survival and proliferation of peripheral T cells. These data thus reveal a conserved and essential role for LKB1 in the proliferative responses of both thymocytes and mature T cells.
Highlights
T-cell proliferation and differentiation in the thymus and the periphery are regulated by the pre-TCR, the mature TCR, cytokines and chemokines [1,2,3]
To determine which stages of thymocyte development were sensitive to LKB1 loss, LckCre1LKB1fl/fl thymi were analyzed for expression of the major histocompatibility complex (MHC) receptors CD4 and CD8
Initial analysis of LckCre1LKB1fl/fl mice showed that LKB1 is essential for T-cell development in the thymus; only cells that fail to delete LKB1 can differentiate in the thymus and generate peripheral T cells
Summary
T-cell proliferation and differentiation in the thymus and the periphery are regulated by the pre-TCR, the mature TCR, cytokines and chemokines [1,2,3]. One other serine/threonine kinase that can regulate cellular responses to energy stress is LKB1 (or serine/threonine kinase 11 -STK11) [12]. This is an evolutionarily conserved kinase: Par, the Caenorhabditis elegans ortholog, is one of the six ‘‘partitioning’’ molecules that control zygote polarity [13] in Drosophila. There is evidence that LKB1 controls the induction of autophagy in response to energy deprivation and sensitizes epithelial cells to c-myc-induced apoptosis [28, 29]
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