LKB1 mediates the development of conventional and innate T cells via AMP-dependent kinase autonomous pathways.

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/ß 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 αß 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.

GTPases and T cell activation.

Guanine nucleotide binding proteins rapidly cycle between a guanosine diphosphate (GDP)-bound and guanosine triphosphate (GTP)-bound state, and they operate as binary switches that control cell activation in response to environmental cues. GTPases adopt different conformations when binding GTP vs. GDP. The GTP-bound state is generally considered to be the active conformation that allows GTPases to interact with downstream effectors and thereby initiate downstream signaling pathways, which regulate many important biological processes. Many members of the Ras family of GTPases, notably Ras and Rap1A, and the Rho family GTPases, Cdc42Hs, Rac1, Rac2 and RhoA, are important components of signal transduction pathways used by antigen receptors, costimulatory, cytokine and chemokine receptors to regulate the immune response. This review discusses current knowledge and ideas about the regulation and function of these GTPases in lymphocytes.

Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling.

T cell receptor (TCR) stimulation activates the small GTPase Rap1A, which is reported to antagonize Ras signaling and induces T cell anergy. To address its role in vivo, we generated transgenic mice that constitutively expressed active Rap1A within the T cell lineage. We found that active Rap1A did not interfere with the Ras signaling pathway or antagonize T cell activation. Instead of anergy, the T lymphocytes that constitutively expressed active Rap1A showed enhanced TCR-mediated responses, both in thymocytes and mature T cells. In addition, Rap1A activation was sufficient to induce strong activation of the beta1 and beta2 integrins via an avidity-modulation mechanism. This shows that, far from playing an inhibitory role during T cell activation, Rap1A positively influences T cells by augmenting lymphocyte responses and directing integrin activation.