Costimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes

被引：58

作者：

Galle-Treger, Lauriane ^{[1
]}

Sankaranarayanan, Ishwarya ^{[1
]}

Hurrell, Benjamin P. ^{[1
]}

Howard, Emily ^{[1
]}

Lo, Richard ^{[1
]}

Maazi, Hadi ^{[1
]}

Lewis, Gavin ^{[2
]}

Banie, Homayon ^{[2
]}

Epstein, Alan L. ^{[3
]}

Hu, Peisheng ^{[3
]}

Rehan, Virender K. ^{[4
]}

Gilliland, Frank D. ^{[5
]}

Allayee, Hooman ^{[6
,7
]}

Soroosh, Pejman ^{[2
]}

Sharpe, Arlene H. ^{[8
]}

Akbari, Omid ^{[1
]}

机构：

[1] Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, 1450 Biggy St,NRT 5509, Los Angeles, CA 90033 USA

[2] Janssen Res & Dev, 3210 Merryfield Row, San Diego, CA 92121 USA

[3] Univ Southern Calif, Keck Sch Med, Dept Pathol, 2011 Zonal Ave HMR, Los Angeles, CA 90033 USA

[4] Harbor UCLA Med Ctr, Div Neonatol, 1000W Carson St, Torrance, CA 90502 USA

[5] Univ Southern Calif, Dept Prevent Med, Div Environm Hlth, 2001 N Soto St,SSB 230G, Los Angeles, CA 90033 USA

[6] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, 2250 Alcazar St,CSC 2202, Los Angeles, CA 90033 USA

[7] Univ Southern Calif, Keck Sch Med, Dept Biochem & Mol Med, 2250 Alcazar St,CSC 2202, Los Angeles, CA 90033 USA

[8] Harvard Med Sch, Dept Microbiol & Immunobiol, 77 Ave Louis Pasteur, Boston, MA 02115 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

美国国家卫生研究院; 瑞士国家科学基金会;

关键词：

ADIPOSE-TISSUE INFLAMMATION; T-CELLS; TNF RECEPTOR; OBESITY; METABOLISM; ACTIVATION; LIGAND; IL-33; EOSINOPHILS; MACROPHAGES;

D O I：

10.1038/s41467-019-08449-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type 2 diabetes mellitus (T2DM). Type-2 innate lymphoid cells (ILC2s) are a recently discovered immune population secreting Th2 cytokines. While previous studies show how ILC2s can play a critical role in the regulation of metabolic homeostasis in the adipose tissue, a therapeutic target capable of modulating ILC2 activation has yet to be identified. Here, we show that GITR, a member of the TNF superfamily, is expressed on both murine and human ILC2s. Strikingly, we demonstrate that GITR engagement of activated, but not naive, ILC2s improves glucose homeostasis, resulting in both protection against insulin resistance onset and amelioration of established insulin-resistance. Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s.

引用

页数：14

共 44 条

[1] Role of immune cells in obesity induced low grade inflammation and insulin resistance [J].

Asghar, Ambreen ;

Sheikh, Nadeem .

CELLULAR IMMUNOLOGY, 2017, 315 :18-26

[2] Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study [J].

Brahimaj, Adela ;

Ligthart, Symen ;

Ghanbari, Mohsen ;

Ikram, Mohammad Arfan ;

Hofman, Albert ;

Franco, Oscar H. ;

Kavousi, Maryam ;

Dehghan, Abbas .

EUROPEAN JOURNAL OF EPIDEMIOLOGY, 2017, 32 (03) :217-226

[3] Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity [J].

Brestoff, Jonathan R. ;

Kim, Brian S. ;

Saenz, Steven A. ;

Stine, Rachel R. ;

Monticelli, Laurel A. ;

Sonnenberg, Gregory F. ;

Thome, Joseph J. ;

Farber, Donna L. ;

Lutfy, Kabirullah ;

Seale, Patrick ;

Artis, David .

NATURE, 2015, 519 (7542) :242-+

[4] Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells [J].

Cautivo, Kelly M. ;

Molofsky, Ari B. .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2016, 46 (06) :1315-1325

[5] Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection [J].

Clouthier, Derek L. ;

Watts, Tania H. .

CYTOKINE & GROWTH FACTOR REVIEWS, 2014, 25 (02) :91-106

[6] Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy [J].

Coe, David ;

Begom, Shaima ;

Addey, Caroline ;

White, Matthew ;

Dyson, Julian ;

Chai, Jian-Guo .

CANCER IMMUNOLOGY IMMUNOTHERAPY, 2010, 59 (09) :1367-1377

[7] Stimulation of the Glucocorticoid-Induced TNF Receptor Family-Related Receptor on CD8 T Cells Induces Protective and High-Avidity T Cell Responses to Tumor-Specific Antigens [J].

Cote, Anik L. ;

Zhang, Peisheng ;

O'Sullivan, Jeremy A. ;

Jacobs, Valerie L. ;

Clemis, Carli R. ;

Sakaguchi, Shimon ;

Guevara-Patino, Jose A. ;

Turk, Mary Jo .

JOURNAL OF IMMUNOLOGY, 2011, 186 (01) :275-283

[8] TRAF4 functions as an intermediate of GITR-induced NF-κB activation [J].

Esparza, EM ;

Arch, RH .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2004, 61 (24) :3087-3092

[9] Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity [J].

Galle-Treger, Lauriane ;

Suzuki, Yuzo ;

Patel, Nisheel ;

Sankaranarayanan, Ishwarya ;

Aron, Jennifer L. ;

Maazi, Hadi ;

Chen, Lin ;

Akbari, Omid .

NATURE COMMUNICATIONS, 2016, 7

[10] Cutting Edge: IL-25 Elicits Innate Lymphoid Type 2 and Type II NKT Cells That Regulate Obesity in Mice [J].

Hams, Emily ;

Locksley, Richard M. ;

McKenzie, Andrew N. J. ;

Fallon, Padraic G. .

JOURNAL OF IMMUNOLOGY, 2013, 191 (11) :5349-5353

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