Lymphocyte Activation Gene-3 Maintains Mitochondrial and Metabolic Quiescence in Naive CD4+ T Cells
Dana M. Previte,
Christina P. Martins,
Erin C. O’Connor,
Meghan L. Marre,
Gina M. Coudriet,
Noah W. Beck,
Ashley V. Menk,
Rebecca H. Wright,
Hubert M. Tse,
Greg M. Delgoffe,
Jon D. Piganelli
Affiliations
Dana M. Previte
Department of Surgery, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA
Christina P. Martins
Department of Surgery, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
Erin C. O’Connor
Department of Surgery, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
Meghan L. Marre
Department of Surgery, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
Gina M. Coudriet
Department of Surgery, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
Noah W. Beck
Department of Surgery, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
Ashley V. Menk
Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh, 5115 Centre Avenue, Pittsburgh, PA 15232, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, 5115 Centre Avenue, Pittsburgh, PA 15232, USA
Rebecca H. Wright
Department of Surgery, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
Hubert M. Tse
Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
Greg M. Delgoffe
Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, Hillman Cancer Center, University of Pittsburgh, 5115 Centre Avenue, Pittsburgh, PA 15232, USA; University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, 5115 Centre Avenue, Pittsburgh, PA 15232, USA
Jon D. Piganelli
Department of Surgery, Rangos Research Center, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Corresponding author
Summary: Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed by CD4+ T cells and tempers their homeostatic expansion. Because CD4+ T cell proliferation is tightly coupled to bioenergetics, we investigate the role of LAG-3 in modulating naive CD4+ T cell metabolism. LAG-3 deficiency enhances the metabolic profile of naive CD4+ T cells by elevating levels of mitochondrial biogenesis. In vivo, LAG-3 blockade partially restores expansion and the metabolic phenotype of wild-type CD4+ T cells to levels of Lag3−/− CD4+ T cells, solidifying that LAG-3 controls these processes. Lag3−/− CD4+ T cells also demonstrate greater signal transducer and activator of transcription 5 (STAT5) activation, enabling resistance to interleukin-7 (IL-7) deprivation. These results implicate this pathway as a target of LAG-3-mediated inhibition. Additionally, enhancement of STAT5 activation, as a result of LAG-3 deficiency, contributes to greater activation potential in these cells. These results identify an additional mode of regulation elicited by LAG-3 in controlling CD4+ T cell responses. : Previte et al. show that LAG-3 expression regulates the metabolic profile of naive CD4+ T cells during homeostatic expansion. They observed that Lag3-deficient CD4+ T cells are resistant to Interleukin-7 deprivation due to enhanced STAT5 activation. Increased STAT5 signaling also mediated greater activation potential in these T cells following stimulation. Keywords: LAG-3, CD4+ T cell, metabolism, mitochondria, STAT5
