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

Lauriane Galle-Treger, Ishwarya Sankaranarayanan, Benjamin P. Hurrell, Emily Howard, Richard Lo, Hadi Maazi, Gavin Lewis, Homayon Banie, Alan L. Epstein, Peisheng Hu, Virender K. Rehan, Frank D. Gilliland, Hooman Allayee, Pejman Soroosh, Arlene H. Sharpe and Omid Akbari ()
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Lauriane Galle-Treger: University of Southern California
Ishwarya Sankaranarayanan: University of Southern California
Benjamin P. Hurrell: University of Southern California
Emily Howard: University of Southern California
Richard Lo: University of Southern California
Hadi Maazi: University of Southern California
Gavin Lewis: Janssen Research and Development
Homayon Banie: Janssen Research and Development
Alan L. Epstein: University of Southern California
Peisheng Hu: University of Southern California
Virender K. Rehan: Harbor-UCLA Medical Center
Frank D. Gilliland: University of Southern California
Hooman Allayee: University of Southern California
Pejman Soroosh: Janssen Research and Development
Arlene H. Sharpe: Harvard Medical School
Omid Akbari: University of Southern California

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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 naïve, 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.

Date: 2019
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DOI: 10.1038/s41467-019-08449-x

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