Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition

Yukiko Tokifuji; Hodaka Hayabuchi; Takashi Sasaki; Mariko Hara-Chikuma; Keiji Hirota; Hayato Takahashi; Masayuki Amagai; Akihiko Yoshimura; Shunsuke Chikuma

doi:10.1016/j.isci.2023.108646

Targeting abatacept-resistant T-helper-17 cells by aldehyde dehydrogenase inhibition

iScience. 2023 Dec 9;27(1):108646. doi: 10.1016/j.isci.2023.108646. eCollection 2024 Jan 19.

Authors

Yukiko Tokifuji¹, Hodaka Hayabuchi¹, Takashi Sasaki², Mariko Hara-Chikuma³, Keiji Hirota⁴, Hayato Takahashi⁵, Masayuki Amagai⁵, Akihiko Yoshimura¹, Shunsuke Chikuma¹

Affiliations

¹ Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, East Lecture Hall 4F, Shinjuku, Tokyo 160-8582, Japan.
² Center for Supercentenarian Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
³ Department of Pharmacology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
⁴ Laboratory of Integrative Biological Science, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
⁵ Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.

Abstract

IL-17-producing helper T (Th17) cells are long-lived and serve as central effector cells in chronic autoimmune diseases. The underlying mechanisms of Th17 persistence remain unclear. We demonstrated that abatacept, a CD28 antagonist, effectively prevented the development of skin disease in a Th17-dependent experimental autoimmune dermatitis model. Abatacept selectively inhibited the emergence of IL-7R-negative effector-phenotype T cells while allowing the survival and proliferation of IL-7R⁺ memory-phenotype cells. The surviving IL-7R⁺ Th17 cells expressed genes associated with alcohol/aldehyde detoxification and showed potential to transdifferentiate into IL-7R-negative effector cells. Inhibiting aldehyde dehydrogenase reduced IL-7R⁺ Th17 cells in vivo, independently of CD28, and exhibited additive effects when combined with abatacept. Our findings suggest that CD28 blockade prevents inflammation without eliminating persistent memory cells. These remaining memory cells can be targeted by other drugs, such as aldehyde dehydrogenase inhibitors, to limit their survival, thereby facilitating the treatment of chronic autoimmune diseases.

Keywords: Cell; Immunity; Molecular biology.