[Title]
A virtual memory CD8(+) T cell-originated subset causes alopecia areata through innate-like cytotoxicity

[Author]
Joon Seok 1,2,9, Sung-Dong Cho1,9, Jeongsoo Lee1, Yunseo Choi1, Su-Young Kim 2, Sung-Min Lee3,4, Sang-Hoon Kim 5, Seongju Jeong 1, Minwoo Jeon1, Hoyoung Lee5, A. Reum Kim1, Baekgyu Choi3, Sang-Jun Ha 6, Inkyung Jung 3, Ki-Jun Yoon3,4, Jong-Eun Park 1, Jong Hoon Kim 7, Beom Joon Kim2, Eui-Cheol Shin 1,5 & Su-Hyung Park 1,8

1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
2Department of Dermatology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
3Department of Biological Science, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
4KAIST Stem Cell Center, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
5The Center for Viral Immunology, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
6Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
7Department of Dermatology and Cutaneous Biology Research Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
8The Center for Epidemic Preparedness, KAIST Institute, Daejeon, Republic of Korea.
9These authors contributed equally: Joon Seok, Sung-Dong Cho. e-mail: ecshin@kaist.ac.kr; park3@kaist.ac.kr

[Journal] 

Nature Immunology volume 24, pages1308–1317 (2023)


[Abstract]
Virtual memory T (T_VM) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although T_VM cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a T_VM cell-originated CD44^{super-high(s-hi)}CD49d^lo CD8⁺ T cell subset with features of tissue residency. These cells are transcriptionally, phenotypically and functionally distinct from conventional CD8⁺ T_VM cells and can cause alopecia areata. Mechanistically, CD44^s-hiCD49d^lo CD8⁺ T cells could be induced from conventional T_VM cells by interleukin (IL)-12, IL-15 and IL-18 stimulation. Pathogenic activity of CD44^s-hiCD49d^lo CD8⁺ T cells was mediated by NKG2D-dependent innate-like cytotoxicity, which was further augmented by IL-15 stimulation and triggered disease onset. Collectively, these data suggest an immunological mechanism through which T_VM cells can cause chronic inflammatory disease by innate-like cytotoxicity.