Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

Abstract

The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphatidylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoimmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity.

Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways

“…5A). This is consistent with previous observations that neglected T cells have reduced nutrient uptake and cell size while T cells that expressed activated Akt have elevated glucose metabolism and increased cell size (8,24). Second, Glut1 transgenic cells also showed an increased ability to produce IL-2 and IFN-␥ during T cell activation.…”

“…Glut1 and myristoylated Akt (mAkt) 3 transgenic mice have been previously described (24,25) and were bred and maintained on the C57BL/6J background (The Jackson Laboratory). Double transgenic mice were produced at Duke University through selective breeding.…”

“…ELISAs were preformed on supernatant from T cell cultures using rat Abs against murine IL-2 and IFN-␥ (BD Pharmingen) as previously described (24). In some cases IL-2 ELISA was performed using Endogen Mouse IL-2 ELISA kit (Pierce Biotechnology) as per the manufacturer's instructions.…”

“…Activation of PI3K may be a particularly important regulator of glucose uptake, as PI3K inhibition prevented increased glucose metabolism after lymphocyte activation or cytokine stimulation, and decreased glucose uptake of leukemic cells (5,(21)(22)(23). Conversely, in addition to its ability to cause autoimmunity and lymphoma, expression of constitutively active Akt promoted increased glucose uptake and consumption in cell lines (20,23) and elevated glycolysis in primary T cells (24). The PI3K/Akt signaling pathway may, therefore, play an important role in regulating the immune response and lymphocyte homeostasis through the regulation of glucose metabolism.…”

γc cytokines provide multiple homeostatic signals to naive CD4+ T cells

“…Since activation of the intracellular kinase PKB (also known as Akt) in response to growth factors can trigger increases in cell size, metabolism and survival in several cellular systems [29,30], it has been proposed that IL-7 may act through PKB to mediate its homeostatic effects. Previous studies have shown that an activated PKB Tg could enhance T cell survival in vivo [31,32], although these Tg mice developed autoimmunity and lymphoma, suggesting PKB-mediated transformation. Moreover, conditional deletion of phosphatase and tension homologue deleted on chromosome 10 that counteracts PKB, can bypass the dependence on IL-7 and pre-TCR signals in developing thymocytes [33], although again these mice developed T cell lymphomas.…”