한빛사논문
ZhengWang Sun, PhD1†, Ji Hye Kim, MS1,8†, Seo Hyeong Kim, PhD1,8, Hye Ran Kim, MS1, KeLun Zhang, MS1,8, Youdong Pan, PhD2, Min Kyung Ko, MS1, Bo Mi Kim, MS1, Howard Chu, MD1, Hee Ra Lee, MD1, Hye Li Kim, MS1,8, Ji Hyung Kim, PhD3, Xiujun Fu, PhD4, Young-Min Hyun, PhD5, Ki Na Yun, MS6, Jin Young Kim, PhD6, Dong Won Lee, MD, PhD7, Seung Yong Song, MD, PhD7, Charles P. Lin, PhD4, Rachael A. Clark, MD, PhD2, Kwang Hoon Lee, MD, PhD1,8*, Thomas S. Kupper, MD2*◊, Chang Ook Park, MD, PhD1,2,8†
1Department of Dermatology & Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
2Department of Dermatology & Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA.
3Division of Biotechnology, College of Life Sciences & Biotechnology, Korea University, Seoul, Korea.
4Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
5Department of Anatomy and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
6Biomedical Omics Group, Korea Basic Science Institute, Ochang 28119, Korea
7Department of Plastic and Reconstructive Surgery, Institute for Human Tissue Restoration, Yonsei University College of Medicine, Seoul, Korea
8Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
†These authors contributed equally to this work.
◊Lead author: Thomas S. Kupper, MD
*Corresponding authors
Abstract
Background
Natural killer T (NKT) cells are unconventional T cells that bridge innate and adaptive immunity. NKT cells have been implicated in the development of atopic dermatitis (AD).
Objective
We aimed to investigate the role of NKT cells in AD development, especially in skin.
Methods
Global proteomic and transcriptomic analyses were performed using human healthy controls (HC) and AD patients’ skin and blood. CXCR4 and CXCL12 expressions in skin NKT cells were analyzed in human AD and mouse AD models. By using parabiosis and intravital imaging, the role of skin CXCR4+ NKT cells was further evaluated in AD mouse models using CXCR conditionally deficient or CXCL12 transgenic mice.
Results
CXCR4 and its cognate ligand CXCL12 were significantly upregulated in human AD skin by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin and were consistently elevated in our AD mouse models. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Predominant skin NKT cells were CXCR4+ and CD69+, similar to tissue-resident memory T (TRM) cells. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in liver, spleen and lymph nodes. Skin fibroblasts were the main source of CXCL12. CXCR4+ NKT cells preferentially trafficked to CXCL12-rich areas, forming an enriched CXCR4+ NKTRM/CXCL12+ cell cluster, which developed in acute and chronic allergic inflammation in our AD mouse models.
Conclusions
CXCR4+ NKTRM cells may form a niche that contributes to atopic dermatitis, where CXCL12 is highly expressed.
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