LKB1 is essential for the proliferation of T‐cell progenitors and mature peripheral T cells

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.

The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression

“…In this study, we identified LKB1 as an essential regulator of intrathymic T-cell development. A very recent publication from the Cantrell lab also reported that deletion of LKB1 prevents T-cell development [36]. Both studies showed that LckCre-mediated deletion of LKB1 in T cells led to reduced thymus size, blocked transition from DN3 to DN4 stage and impaired generation of CD4 SP and CD8 SP thymocytes.…”

Energy addiction and lymphocyte differentiation: A new role for the liver kinase B1 kinase

“…In this issue of the European Journal of Immunology, Tamas et al attempt to identify a novel ''master regulator'' of lymphocyte growth and metabolism by genetically targeting the liver kinase B1 (LKB1) [6]. LKB1 is a serine-threonine kinase that regulates a number of important kinases of the AMP-activated protein kinase (AMPK) family [7].…”

“…Interestingly, T-cell-specific LKB1 deletion does not lead to transformation but to severe effects on cell growth, proliferation, and progenitor maturation [6]. Lck-Cre-mediated deletion of LKB1 leads to an almost complete suppression of intrathymic development [6].…”

“…Lck-Cre-mediated deletion of LKB1 leads to an almost complete suppression of intrathymic development [6]. LKB1 À/À progenitors are arrested at the…”

“…In LKB1 À/À pre-T cells, the pre-TCR is intact as demonstrated by efficient TCR-b selection; however, specific downstream signaling cascades (i.e. S6 kinase activation) were inactivated, and the activation of AMPK was also impaired [6]. As a consequence, survival of pre-TCR-expressing thymocytes is severely affected, leading to significantly enhanced levels of apoptosis.…”