Human CD4+ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses

Nikhila S Bharadwaj; Nicholas A Zumwalde; Arvinder Kapur; Manish Patankar; Jenny E Gumperz

doi:10.1016/j.isci.2024.109775

Human CD4⁺ memory phenotype T cells use mitochondrial metabolism to generate sensitive IFN-γ responses

iScience. 2024 Apr 18;27(5):109775. doi: 10.1016/j.isci.2024.109775. eCollection 2024 May 17.

Authors

Nikhila S Bharadwaj¹, Nicholas A Zumwalde², Arvinder Kapur³, Manish Patankar⁴, Jenny E Gumperz¹

Affiliations

¹ Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health; Madison, WI 53706, USA.
² Department of Genetics, University of Wisconsin School of Medicine and Public Health; Madison, WI 53706, USA.
³ QIAGEN Sciences Inc., 19300 Germantown Road, Germantown, MD 20874, USA.
⁴ Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health; Madison, WI 53706, USA.

Abstract

The transition of naive T lymphocytes into antigenically activated effector cells is associated with a metabolic shift from oxidative phosphorylation to aerobic glycolysis. This shift facilitates production of the key anti-tumor cytokine interferon (IFN)-γ; however, an associated loss of mitochondrial efficiency in effector T cells ultimately limits anti-tumor immunity. Memory phenotype (MP) T cells are a newly recognized subset that arises through homeostatic activation signals following hematopoietic transplantation. We show here that human CD4⁺ MP cell differentiation is associated with increased glycolytic and oxidative metabolic activity, but MP cells retain less compromised mitochondria compared to effector CD4⁺ T cells, and their IFN-γ response is less dependent on glucose and more reliant on glutamine. MP cells also produced IFN-γ more efficiently in response to weak T cell receptor (TCR) agonism than effectors and mediated stronger responses to transformed B cells. MP cells may thus be particularly well suited to carry out sustained immunosurveillance against neoplastic cells.

Keywords: cell biology; immunity.