Anti-AMPK1 was a kind gift of Grahame Hardie, University of Dundee. AMP-activated protein kinase (AMPK). The present study now analyses the impact of AMPK deletion in DP thymocytes and shows that the role of LKB1 during the development of both conventional and innate T cells is mediated by AMPK-independent pathways. Introduction The adaptive immune response is mediated by T cells that express T cell antigen receptor complexes comprising of highly variable TCR and subunits . These T cells can be subdivided into cells that express CD8, the receptor for major histocompatibility antigen complex I (MHC class I), and cells that express CD4, the receptor for MHC class II molecules. CD4 positive T cells can be further subdivided into conventional CD4 T cells, regulatory T cells (Tregs) and Natural Killer T (NKT) cells . Conventional CD4 and CD8 T cells express / TCR complexes that recognize peptide/MHC complexes whereas NKT cells express an invariant V14 T cell receptor that recognize glycolipid/CD1d antigen complexes (iNKTs) and play a role in immune surveillance and immune homeostasis . CD8 T cells can also be subdivided into conventional CD8 cells that express a CD8 heterodimer and CD8 T cell populations that express a CD8 homodimer . TCR+ CD8+ conventional T cells recirculate between the blood, LEQ506 secondary lymphoid tissue and the lymphatics and respond to immune activation and differentiate to produce cytolytic effector cells. TCR+ CD8+ T cells are typically found in the epithelial layer in the gut and play a role in regulating inflammatory immune responses in the gut . The balanced production of different T cell subpopulations, each with unique functions, during thymus development is essential to ensure the function and LEQ506 the homeostasis of the peripheral immune system. Hence, understanding the nature of the signals required for the development of different T cell subpopulations is important. All T cells LEQ506 that express TCR complexes develop in the thymus from progenitors that lack expression of CD4 and CD8, hence termed double negative (DN) thymocytes. At the DN stage of thymocyte development T cell progenitors undergo genetic rearrangement of the TCR locus, which leads to the expression of a pre-TCR complex. This immature TCR complex drives DNs to proliferate and differentiate into CD4/8 double positive (DP) thymocytes. DP thymocytes that have successfully re-arranged their TCR chain will undergo a selection process and differentiate to conventional TCR CD4+ or CD8+ T cells, NKT cells or TCR+ CD8+ gut lymphocytes. In this context, there is currently considerable interest in understanding the signalling DLL4 pathways that control metabolic checkpoints in T lymphocytes. It is thus relevant that recent studies have shown that the serine/threonine kinase LKB1 (Liver kinase B1 also known as serine/threonine kinase 11 – STK11) is important in controlling metabolic homeostasis in early T cell progenitors in the thymus , . There is also evidence that LKB1 is important in CD4/CD8 DPs. LKB1 null DPs thus appear to be unable to develop into conventional TCR/ CD4+ and CD8+ T cells , . However, there are a number of important unanswered questions about LKB1 and its role in thymus development. For example, is LKB1 required for DP thymocyte survival and does this explain why LKB1 null DPs cannot produce mature SP T cells? To date most studies of LKB1 in DP thymocytes have studied the few DPs that survive LKB1 deletion at the thymocyte progenitor LEQ506 stage and have not looked at the immediate impact of LKB1 loss in DPs. One other question is whether LKB1 is important in non-conventional T cells, i.e. TCR+ CD8+ IELs or TCR+ CD4+ iNKTs? In this respect it is evident that LKB1 is not essential for all T cells. For example, LKB1 has an obligatory role to control survival of T cell progenitors , LEQ506  but is not essential for the metabolic control of quiescent naive T cells in the periphery . One other fundamental question is how does LKB1 control T cell development? One proposal is that LKB1 controls thymocyte development via regulation of the adenosine monophosphate (AMP)-activated protein kinase 1 (AMPK1) . This kinase is phosphorylated and activated by LKB1 in response to cellular energy stresses that cause increases in cellular AMP:ATP ratios . It is a candidate to mediate the role of LKB1 in thymocyte development because in many cell lineages AMPK1 acts to restore cellular energy balance by terminating ATP.
- For the T-175 flask, the quantity of quenching and trypsin reagent was adjusted to 7
- In this examine, we summarize the usage of MAP4Ks and DUSPs in T cells as biomarkers and/or therapeutic focuses on for SLE (Shape 1)