Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma.
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.
Rathmell
Jeffrey C
JC
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, USA.
Elstrom
Rebecca L
RL
Cinalli
Ryan M
RM
Thompson
Craig B
CB
D000818:Animals; D015551:Autoimmunity; D018106:CD28 Antigens / Q000378:metabolism; D002455:Cell Division; D048429:Cell Size; D006019:Glycolysis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007399:Interphase; D016399:Lymphoma, T-Cell / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D018106:CD28 Antigens; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D007371:Interferon-gamma; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt