LKB1 Mediates the Development of Conventional and Innate T Cells via AMP-Dependent Kinase Autonomous Pathways

Marouan Zarrouk,Julia Rolf,Doreen Ann Cantrell,Jose Alberola-Ila

doi:10.1371/journal.pone.0060217

Abstract

The present study has examined the role of the serine/threonine kinase LKB1 in the survival and differentiation of CD4/8 double positive thymocytes. LKB1-null DPs can respond to signals from the mature α/β T-cell-antigen receptor and initiate positive selection. However, in the absence of LKB1, thymocytes fail to mature to conventional single positive cells causing severe lymphopenia in the peripheral lymphoid tissues. LKB1 thus appears to be dispensable for positive selection but important for the maturation of positively selected thymocytes. LKB1 also strikingly prevented the development of invariant Vα14 NKT cells and innate TCR αβ gut lymphocytes. Previous studies with gain of function mutants have suggested that the role of LKB1 in T cell development is mediated by its substrate the 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.

Highlights

The adaptive immune response is mediated by T cells that express T cell antigen receptor complexes comprising of highly variable TCRa and b subunits [1]
Previous studies have shown that LKB1 controls the survival of T cell progenitors at the double negative (DN) stage of development
In LckCre LKB1fl/fl mice a few double positive (DP) thymocytes survive the early deletion of LKB1 and become DP thymocytes [6]

Summary

Introduction

The adaptive immune response is mediated by T cells that express T cell antigen receptor complexes comprising of highly variable TCRa and b subunits [1]. 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. Conventional CD4 and CD8 T cells express a/b TCR complexes that recognize peptide/MHC complexes whereas NKT cells express an invariant Va14 T cell receptor that recognize glycolipid/CD1d antigen complexes (iNKTs) and play a role in immune surveillance and immune homeostasis [3]. TCRab+ CD8aa+ T cells are typically found in the epithelial layer in the gut and play a role in regulating inflammatory immune responses in the gut [5]

Methods

Results

Conclusion