IL-7Rα <sup>low</sup> CD8 <sup>+</sup> T Cells from Healthy Individuals Are Anergic with Defective Glycolysis

Abstract

Effector memory (EM) CD8+ T cells expressing lower levels of interleukin-7 receptor alpha (IL-7Rαlow) from healthy individuals are partly compromised in vitro, but the identity of these cells has remained unclear. Here, we demonstrate that IL-7Rαlow EM CD8+ T cells are naturally occurring anergic cells in vivo, impaired in proliferation and IL-2 production, but competent in IFN-γ and TNF-α production, a state that can be restored by IL-2 stimulation. IL-7Rαlow EM CD8+ T cells show decreased expression of GATA3 and c-MYC and are defective in metabolic reprogramming towards glycolysis, a process required for the proliferation of T cells. In particular, mouse IL-7Rαlow memory CD8+ T cells show anergic phenotypes similar to those in humans, but induce severe graft-versus-host disease upon allogeneic T-cell transplantation, suggesting that these cells can be restored to normality or increased activity by inflammatory conditions and may serve as a reservoir for functional immunity. Funding Statement: This work was supported in part by the Creative-Pioneering Researchers Program through Seoul National University (to H.-R. Kim); the Korea Healthcare Technology Research and Development Project, Ministry for Health, Welfare, and Family Affairs (HI17C0534 to H.-R. Kim); the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MOE) (2017R1A4A1015745 to H.-R. Kim); and the SK Telecom Research Fund (3420130260 to H.-R. Kim). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This work was approved by the Institutional Review Boards of Seoul National University Hospital (# 0905-014-280) and Samsung Medical Center (# 2015-09-053). Written informed consent was obtained from all subjects, in accordance with the Declaration of Helsinki. All experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) of Seoul National University (IACUC No. SNU-171024-1-3 and SNU-171206-1-1). All experiments were performed in accordance with the IACUC guidelines of Seoul National University.