Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis

Zheng Wang Sun; Ji Hye Kim; Seo Hyeong Kim; Hye Ran Kim; Ke Lun Zhang; Youdong Pan; Min Kyung Ko; Bo Mi Kim; Howard Chu; Hee Ra Lee; Hye Li Kim; Ji Hyung Kim; Xiujun Fu; Young Min Hyun; Ki Na Yun; Jin Young Kim; Dong Won Lee; Seung Yong Song; Charles P. Lin; Rachael A. Clark; Kwang Hoon Lee; Thomas S. Kupper; Chang Ook Park

doi:10.1016/j.jaci.2020.11.049

Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis

Zheng Wang Sun, Ji Hye Kim, Seo Hyeong Kim, Hye Ran Kim, Ke Lun Zhang, Youdong Pan, Min Kyung Ko, Bo Mi Kim, Howard Chu, Hee Ra Lee, Hye Li Kim, Ji Hyung Kim, Xiujun Fu, Young Min Hyun, Ki Na Yun, Jin Young Kim, Dong Won Lee, Seung Yong Song, Charles P. Lin, Rachael A. ClarkKwang Hoon Lee, Thomas S. Kupper, Chang Ook Park

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

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 by using skin and blood from human healthy–controls and patients with AD. Levels of CXCR4 and CXCL12 expression 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 models of mice with AD by using CXCR4–conditionally deficient or CXCL12 transgenic mice. Results: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4⁺ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4⁺ and CD69⁺. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the 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⁺ tissue-resident NKT cells/CXCL12⁺ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. Conclusions: CXCR4⁺ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.

Original language	English
Pages (from-to)	1764-1777
Number of pages	14
Journal	Journal of Allergy and Clinical Immunology
Volume	147
Issue number	5
DOIs	https://doi.org/10.1016/j.jaci.2020.11.049
Publication status	Published - 2021 May

Bibliographical note

Funding Information:
Supported by National Institutes of Health grants R01AI041707 (to T.S.K.), R01AI127654 (to T.S.K.), TR01AI097128 (to T.S.K. and R.A.C.), and R01AR063962 (to R.A.C.), the National Research Foundation of Korea grant funded by the Korea government ( Ministry of Science and ICT ) (No. NRF-2017R1A2B4009568 [to C.O.P.]), grants of the Korean Health Technology R&D Project , Ministry of Health and Welfare , Republic of Korea (grant HI14C1324 [to K.H.L and C.O.P.] and grant HI14C1799 [to C.O.P.]), the Dongwha Faculty Research Assistance Program of Yonsei University College of Medicine ( 6-2016-0129 [to C.O.P.]), and an Amorepacific grant (2018 [to C.O.P.]).

Publisher Copyright:
© 2021 American Academy of Allergy, Asthma & Immunology

Keywords

Atopic dermatitis
CXCL12
CXCR4
T cells
natural killer T cells
thymic stromal lymphopoietin
tissue-resident memory T cells

ASJC Scopus subject areas

Immunology and Allergy
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jaci.2020.11.049

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Sun, Z. W., Kim, J. H., Kim, S. H., Kim, H. R., Zhang, K. L., Pan, Y., Ko, M. K., Kim, B. M., Chu, H., Lee, H. R., Kim, H. L., Kim, J. H., Fu, X., Hyun, Y. M., Yun, K. N., Kim, J. Y., Lee, D. W., Song, S. Y., Lin, C. P., ... Park, C. O. (2021). Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis. Journal of Allergy and Clinical Immunology, 147(5), 1764-1777. https://doi.org/10.1016/j.jaci.2020.11.049

Sun, ZW, Kim, JH, Kim, SH, Kim, HR, Zhang, KL, Pan, Y, Ko, MK, Kim, BM, Chu, H, Lee, HR, Kim, HL, Kim, JH, Fu, X, Hyun, YM, Yun, KN, Kim, JY, Lee, DW, Song, SY, Lin, CP, Clark, RA, Lee, KH, Kupper, TS & Park, CO 2021, 'Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis', Journal of Allergy and Clinical Immunology, vol. 147, no. 5, pp. 1764-1777. https://doi.org/10.1016/j.jaci.2020.11.049

@article{ab8db8ecc5df4ea29c80c3c589934a78,

title = "Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis",

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 by using skin and blood from human healthy–controls and patients with AD. Levels of CXCR4 and CXCL12 expression 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 models of mice with AD by using CXCR4–conditionally deficient or CXCL12 transgenic mice. Results: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the 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+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. Conclusions: CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.",

keywords = "Atopic dermatitis, CXCL12, CXCR4, T cells, natural killer T cells, thymic stromal lymphopoietin, tissue-resident memory T cells",

author = "Sun, {Zheng Wang} and Kim, {Ji Hye} and Kim, {Seo Hyeong} and Kim, {Hye Ran} and Zhang, {Ke Lun} and Youdong Pan and Ko, {Min Kyung} and Kim, {Bo Mi} and Howard Chu and Lee, {Hee Ra} and Kim, {Hye Li} and Kim, {Ji Hyung} and Xiujun Fu and Hyun, {Young Min} and Yun, {Ki Na} and Kim, {Jin Young} and Lee, {Dong Won} and Song, {Seung Yong} and Lin, {Charles P.} and Clark, {Rachael A.} and Lee, {Kwang Hoon} and Kupper, {Thomas S.} and Park, {Chang Ook}",

note = "Funding Information: Supported by National Institutes of Health grants R01AI041707 (to T.S.K.), R01AI127654 (to T.S.K.), TR01AI097128 (to T.S.K. and R.A.C.), and R01AR063962 (to R.A.C.), the National Research Foundation of Korea grant funded by the Korea government ( Ministry of Science and ICT ) (No. NRF-2017R1A2B4009568 [to C.O.P.]), grants of the Korean Health Technology R&D Project , Ministry of Health and Welfare , Republic of Korea (grant HI14C1324 [to K.H.L and C.O.P.] and grant HI14C1799 [to C.O.P.]), the Dongwha Faculty Research Assistance Program of Yonsei University College of Medicine ( 6-2016-0129 [to C.O.P.]), and an Amorepacific grant (2018 [to C.O.P.]). Publisher Copyright: {\textcopyright} 2021 American Academy of Allergy, Asthma & Immunology",

year = "2021",

month = may,

doi = "10.1016/j.jaci.2020.11.049",

language = "English",

volume = "147",

pages = "1764--1777",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

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TY - JOUR

T1 - Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis

AU - Sun, Zheng Wang

AU - Kim, Ji Hye

AU - Kim, Seo Hyeong

AU - Kim, Hye Ran

AU - Zhang, Ke Lun

AU - Pan, Youdong

AU - Ko, Min Kyung

AU - Kim, Bo Mi

AU - Chu, Howard

AU - Lee, Hee Ra

AU - Kim, Hye Li

AU - Kim, Ji Hyung

AU - Fu, Xiujun

AU - Hyun, Young Min

AU - Yun, Ki Na

AU - Kim, Jin Young

AU - Lee, Dong Won

AU - Song, Seung Yong

AU - Lin, Charles P.

AU - Clark, Rachael A.

AU - Lee, Kwang Hoon

AU - Kupper, Thomas S.

AU - Park, Chang Ook

N1 - Funding Information: Supported by National Institutes of Health grants R01AI041707 (to T.S.K.), R01AI127654 (to T.S.K.), TR01AI097128 (to T.S.K. and R.A.C.), and R01AR063962 (to R.A.C.), the National Research Foundation of Korea grant funded by the Korea government ( Ministry of Science and ICT ) (No. NRF-2017R1A2B4009568 [to C.O.P.]), grants of the Korean Health Technology R&D Project , Ministry of Health and Welfare , Republic of Korea (grant HI14C1324 [to K.H.L and C.O.P.] and grant HI14C1799 [to C.O.P.]), the Dongwha Faculty Research Assistance Program of Yonsei University College of Medicine ( 6-2016-0129 [to C.O.P.]), and an Amorepacific grant (2018 [to C.O.P.]). Publisher Copyright: © 2021 American Academy of Allergy, Asthma & Immunology

PY - 2021/5

Y1 - 2021/5

N2 - 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 by using skin and blood from human healthy–controls and patients with AD. Levels of CXCR4 and CXCL12 expression 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 models of mice with AD by using CXCR4–conditionally deficient or CXCL12 transgenic mice. Results: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the 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+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. Conclusions: CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.

AB - 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 by using skin and blood from human healthy–controls and patients with AD. Levels of CXCR4 and CXCL12 expression 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 models of mice with AD by using CXCR4–conditionally deficient or CXCL12 transgenic mice. Results: CXCR4 and its cognate ligand CXCL12 were significantly upregulated in the skin of humans with AD by global transcriptomic and proteomic analyses. CXCR4+ NKT cells were enriched in AD skin, and their levels were consistently elevated in our models of mice with AD. Allergen-induced NKT cells participate in cutaneous allergic inflammation. Similar to tissue-resident memory T cells, the predominant skin NKT cells were CXCR4+ and CD69+. Skin-resident NKT cells uniquely expressed CXCR4, unlike NKT cells in the 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+ tissue-resident NKT cells/CXCL12+ cell cluster that developed in acute and chronic allergic inflammation in our models of mice with AD. Conclusions: CXCR4+ tissue-resident NKT cells may form a niche that contributes to AD, in which CXCL12 is highly expressed.

KW - Atopic dermatitis

KW - CXCL12

KW - CXCR4

KW - T cells

KW - natural killer T cells

KW - thymic stromal lymphopoietin

KW - tissue-resident memory T cells

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U2 - 10.1016/j.jaci.2020.11.049

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M3 - Article

C2 - 33516870

AN - SCOPUS:85101686979

SN - 0091-6749

VL - 147

SP - 1764

EP - 1777

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 5

ER -

Skin-resident natural killer T cells participate in cutaneous allergic inflammation in atopic dermatitis

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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