Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways.
T cell activation potently stimulates cellular metabolism to support the elevated energetic and biosynthetic demands of growth, proliferation, and effector function. We show that glucose uptake is limiting in T cell activation and that CD28 costimulation is required to allow maximal glucose uptake following TCR stimulation by up-regulating expression and promoting the cell surface trafficking of the glucose transporter Glut1. Regulation of T cell glucose uptake and Glut1 was critical, as low glucose prevented appropriate T cell responses. Additionally, transgenic expression of Glut1 augmented T cell activation, and led to accumulation of readily activated memory-phenotype T cells with signs of autoimmunity in aged mice. To further examine the regulation of glucose uptake, we analyzed CD28 activation of Akt, which appeared necessary for maximal glucose uptake of stimulated cells and which we have shown can promote Glut1 cell surface trafficking. Consistent with a role for Akt in Glut1 trafficking, transgenic expression of constitutively active myristoylated Akt increased glucose uptake of resting T cells, but did not alter Glut1 protein levels. Therefore, CD28 appeared to promote Akt-independent up-regulation of Glut1 and Akt-dependent Glut1 cell surface trafficking. In support of this model, coexpression of Glut1 and myristoylated Akt transgenes resulted in a synergistic increase in glucose uptake and accumulation of activated T cells in vivo that were largely independent of CD28. Induction of Glut1 protein and Akt regulation of Glut1 trafficking are therefore separable functions of CD28 costimulation that cooperate to promote glucose metabolism for T cell activation and proliferation.
Jacobs
Sarah R
SR
Department of Pharmacology and Cancer Biology, Sarah W Stedman Center for Nutrition and Metabolism, Duke University Medical Center, Durham, NC 27710, USA.
Herman
Catherine E
CE
Maciver
Nancie J
NJ
Wofford
Jessica A
JA
Wieman
Heather L
HL
Hammen
Jeremy J
JJ
Rathmell
Jeffrey C
JC
D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D048429:Cell Size; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D018106:CD28 Antigens; D016207:Cytokines; D027342:Excitatory Amino Acid Transporter 2; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose