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

doi:10.1016/j.celrep.2019.03.004

Lymphocyte Activation Gene-3 Maintains Mitochondrial and Metabolic Quiescence in Naive CD4⁺ T Cells

Cell Rep. 2019 Apr 2;27(1):129-141.e4. doi: 10.1016/j.celrep.2019.03.004.

Affiliations

¹ 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.
² Department of Surgery, Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
³ 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.
⁴ Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA.
⁵ 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. Electronic address: jdp51@pitt.edu.

PMID: 30943396
DOI: 10.1016/j.celrep.2019.03.004

Abstract

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.

Keywords: CD4(+) T cell; LAG-3; STAT5; metabolism; mitochondria.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / genetics
Antigens, CD / physiology*
CD4-Positive T-Lymphocytes* / cytology
CD4-Positive T-Lymphocytes* / metabolism
CD4-Positive T-Lymphocytes* / ultrastructure
Cells, Cultured
Energy Metabolism / genetics*
Female
Lymphocyte Activation / genetics
Lymphocyte Activation Gene 3 Protein
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / genetics
Mitochondria / metabolism
Mitochondria / physiology*
Organelle Biogenesis*
Resting Phase, Cell Cycle / genetics

Substances

Antigens, CD
Lymphocyte Activation Gene 3 Protein
Lag3 protein, mouse