Metabolic control of T cell receptor signalling (360G-Wellcome-110229_Z_15_Z)

T cell receptor (TCR) activation is essential for the effector functions and proliferative potential of T lymphocytes. Optimal TCR responsiveness requires assembly of the TCR signalosome, a super-molecular signaling complex that couples external antigenic cues to intracellular biochemical events. I discovered that spontaneous activation of the metabolic master regulator AMPK induces loss of the TCR signalosome from human senescent T cells, a novel hallmark of human ageing. This suggested the exi stence of an unrecognized link between changes in T cell metabolism and TCR responsiveness. I also identified cross-talk between AMPK and p38 MAPK signaling that regulates both senescent features and metabolic demands of T cells. Whether intervention at the point of energy sensing pathways may restore TCR functional activity in senescent T cells is not known. Here I propose that the modulation of metabolic pathways by disrupting the AMPK-MAPK signaling axis would restore TCR function. Restoring TCR responsiveness in senescent T cells would offer novel ways to recover T cell activity among the elderly population that suffers from increased susceptibility of opportunistic infections and cancer. Furthermore, since T cells undergo metabolic impairment during an immune response, these studies may have relevance for boosting non senescent T cell responsiveness in vivo.