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

Abstract

Lymphocyte development is a process in which proliferation is coupled to differentiation. In order to undergo efficient proliferation, lymphocytes must coordinate the entry into cell cycle with increased metabolism. The signaling pathways, like those downstream of antigen and cytokine receptors, and specific regulators that directly control cell metabolism are only beginning to be defined. A study in this issue of the European Journal of Immunology, demonstrates that the liver kinase B1 (LKB1) is a regulator of cellular metabolism. Deficiency in LKB1 results in a block in T-cell differentiation, increased apoptosis, as well as impaired survival of mature T cells. This study highlights the importance of LKB1 in T-cell development and function, but as discussed in this Commentary, a number of intriguing questions concerning the regulation and additional functions of LKB1 remain.

The eIF2 Kinase GCN2 Is Essential for the Murine Immune System to Adapt to Amino Acid Deprivation by Asparaginase

“…Lymphocyte development is a process in which proliferation is coupled to differentiation. To undergo efficient proliferation, lymphocytes must coordinate entry into the cell cycle with increased metabolism (35). This is consistent with the idea that amino acid deprivation would be particularly stressful during lymphocyte development.…”

Metabolic remodeling in early development and cardiomyocyte maturation

“…The nematode C. elegans exhibits specialized intermediary metabolism in long-lived mutants and Dauer states, involving glycolytic, glyoxyate, branched chain amino acid, and fumarate metabolism [10–12]. In mammalian systems, redox state and hypoxia regulate self-renewal and mesoderm specification [13–16], while T lymphocyte differentiation requires the bioenergetic sensor pathway involving LKB1 and AMPK [17,18]. The signals arising from metabolic programs include redox and reactive oxygen species, as well as metabolic intermediates [19–22], allowing for a wide variety signaling mechanisms involved in the regulation and the effect of metabolic signatures in cell fate and maturation.…”

LKB1 loss of function studied in vivo

“…Recently, two separate groups have described Lkb1 loss in T‐cells. They both used Cre‐recombinase with expression driven by the lymphocyte protein tyrosine kinase (Lck) promoter to generate LckCre + Lkb1 fl/fl mice [120–122]. Although the mice were viable, they had reduced numbers of thymocytes, substantial amounts of T‐cell death and very small thymi with abnormal tissue architecture [120,121].…”