| First Author | MacIver NJ | Year | 2011 |
| Journal | J Immunol | Volume | 187 |
| Issue | 8 | Pages | 4187-98 |
| PubMed ID | 21930968 | Mgi Jnum | J:179301 |
| Mgi Id | MGI:5301760 | Doi | 10.4049/jimmunol.1100367 |
| Citation | MacIver NJ, et al. (2011) The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J Immunol 187(8):4187-98 |
| abstractText | T cell activation leads to engagement of cellular metabolic pathways necessary to support cell proliferation and function. However, our understanding of the signal transduction pathways that regulate metabolism and their impact on T cell function remains limited. The liver kinase B1 (LKB1) is a serine/threonine kinase that links cellular metabolism with cell growth and proliferation. In this study, we demonstrate that LKB1 is a critical regulator of T cell development, viability, activation, and metabolism. T cell-specific ablation of the gene that encodes LKB1 resulted in blocked thymocyte development and a reduction in peripheral T cells. LKB1-deficient T cells exhibited defects in cell proliferation and viability and altered glycolytic and lipid metabolism. Interestingly, loss of LKB1 promoted increased T cell activation and inflammatory cytokine production by both CD4(+) and CD8(+) T cells. Activation of the AMP-activated protein kinase (AMPK) was decreased in LKB1-deficient T cells. AMPK was found to mediate a subset of LKB1 functions in T lymphocytes, as mice lacking the alpha1 subunit of AMPK displayed similar defects in T cell activation, metabolism, and inflammatory cytokine production, but normal T cell development and peripheral T cell homeostasis. LKB1- and AMPKalpha1-deficient T cells each displayed elevated mammalian target of rapamycin complex 1 signaling and IFN-gamma production that could be reversed by rapamycin treatment. Our data highlight a central role for LKB1 in T cell activation, viability, and metabolism and suggest that LKB1-AMPK signaling negatively regulates T cell effector function through regulation of mammalian target of rapamycin activity. |
