The chemokine CCL5 regulates glucose uptake and AMP kinase signaling in activated T cells to facilitate chemotaxis.
Recruitment of effector T cells to sites of infection or inflammation is essential for an effective adaptive immune response. The chemokine CCL5 (RANTES) activates its cognate receptor, CCR5, to initiate cellular functions, including chemotaxis. In earlier studies, we reported that CCL5-induced CCR5 signaling activates the mTOR/4E-BP1 pathway to directly modulate mRNA translation. Specifically, CCL5-mediated mTOR activation contributes to T cell chemotaxis by initiating the synthesis of chemotaxis-related proteins. Up-regulation of chemotaxis-related proteins may prime T cells for efficient migration. It is now clear that mTOR is also a central regulator of nutrient sensing and glycolysis. Herein we describe a role for CCL5-mediated glucose uptake and ATP accumulation to meet the energy demands of chemotaxis in activated T cells. We provide evidence that CCL5 is able to induce glucose uptake in an mTOR-dependent manner. CCL5 treatment of ex vivo activated human CD3(+) T cells also induced the activation of the nutrient-sensing kinase AMPK and downstream substrates ACC-1, PFKFB-2, and GSK-3β. Using 2-deoxy-d-glucose, an inhibitor of glucose uptake, and compound C, an inhibitor of AMPK, experimental data are presented that demonstrate that CCL5-mediated T cell chemotaxis is dependent on glucose, as these inhibitors inhibit CCL5-mediated chemotaxis in a dose-dependent manner. Altogether, these findings suggest that both glycolysis and AMPK signaling are required for efficient T cell migration in response to CCL5. These studies extend the role of CCL5 mediated CCR5 signaling beyond lymphocyte chemotaxis and demonstrate a role for chemokines in promoting glucose uptake and ATP production to match energy demands of migration.
Toronto General Research Institute, University Health Network and Department of Immunology, University of Toronto, Toronto, Ontario M5G 2M1, Canada.
Olivia
O
Chan
J Daniel
JD
Burke
Darrin F
DF
Gao
Eleanor N
EN
Fish
D000123:Acetyltransferases / Q000276:immunology / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000276:immunology / Q000378:metabolism; D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005947:Glucose / Q000276:immunology / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D025481:Phosphofructokinase-2 / Q000276:immunology / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
C483024:CCL5 protein, human; D018946:Chemokine CCL5; D011720:Pyrazoles; D011743:Pyrimidines; D019713:Receptors, CCR5; C516138:dorsomorphin; D000255:Adenosine Triphosphate; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; C555744:PFKFB2 protein, human; D025481:Phosphofructokinase-2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000263:Adenylate Kinase; D005947:Glucose