γδ T Cells Producing Interleukin-17A Regulate Adipose Regulatory T Cell Homeostasis and Thermogenesis

Overview

Journal Nat Immunol

Date 2018 Apr 20

PMID 29670241

Citations 167

Authors

Ayano C Kohlgruber

Shani T Gal-Oz

Nelson M LaMarche

Moto Shimazaki

Danielle Duquette

Hui-Fern Koay

Hung N Nguyen

Amir I Mina

Tyler Paras

Ali Tavakkoli

Ulrich von Andrian

Adam P Uldrich

Dale I Godfrey

Alexander S Banks

Tal Shay

Michael B Brenner

Lydia Lynch

Affiliations

Soon will be listed here.

Abstract

γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (T) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα and Pdpn stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2 T cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control.

Citing Articles

Neurotensin-neurotensin receptor 2 signaling in adipocytes suppresses food intake through regulating ceramide metabolism.

Fu W, Lai Y, Li K, Yang Y, Guo X, Gong Q Cell Res. 2025; 35(2):117-131.

PMID: 39748047 PMC: 11770130. DOI: 10.1038/s41422-024-01038-8.

Identification of specific microbiota members that induce beige fat biogenesis in response to dietary cues.

Honda K, Tanoue T, Nagayama M, Roochana A, Zimmerman S, Ashenberg O Res Sq. 2024; .

PMID: 39678347 PMC: 11643319. DOI: 10.21203/rs.3.rs-5454144/v1.

γδ T cells in hematological malignancies: mechanisms and therapeutic strategies.

Chen X, Sun G, Zhu X Blood Sci. 2024; 7(1):e00213.

PMID: 39676818 PMC: 11637750. DOI: 10.1097/BS9.0000000000000213.

Metabolomics analysis reveals resembling metabolites between humanized γδ TCR mice and human plasma.

Michael H, Weng G, Vallas M, Lovos D, Chen E, Sheiffele P Sci Rep. 2024; 14(1):29321.

PMID: 39592837 PMC: 11599612. DOI: 10.1038/s41598-024-81003-y.

Upregulation of inhibitor of DNA binding 1 and 3 is important for efficient thermogenic response in human adipocytes.

Arianti R, Vinnai B, Alrifai R, Karadsheh G, Al-Khafaji Y, Poliska S Sci Rep. 2024; 14(1):28272.

PMID: 39550428 PMC: 11569133. DOI: 10.1038/s41598-024-79634-2.

References

Zeyda M, Wernly B, Demyanets S, Kaun C, Hammerle M, Hantusch B . Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue. Int J Obes (Lond). 2012; 37(5):658-65. DOI: 10.1038/ijo.2012.118. View

Van Dyken S, Mohapatra A, Nussbaum J, Molofsky A, Thornton E, Ziegler S . Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells. Immunity. 2014; 40(3):414-24. PMC: 4019510. DOI: 10.1016/j.immuni.2014.02.003. View

Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson S . PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012; 486(7404):549-53. PMC: 3387339. DOI: 10.1038/nature11132. View

Kuswanto W, Burzyn D, Panduro M, Wang K, Jang Y, Wagers A . Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells. Immunity. 2016; 44(2):355-67. PMC: 4764071. DOI: 10.1016/j.immuni.2016.01.009. View

Wood I, Wang B, Trayhurn P . IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytes. Biochem Biophys Res Commun. 2009; 384(1):105-9. DOI: 10.1016/j.bbrc.2009.04.081. View

Vantourout P, Hayday A . Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol. 2013; 13(2):88-100. PMC: 3951794. DOI: 10.1038/nri3384. View

Brestoff J, Kim B, Saenz S, Stine R, Monticelli L, Sonnenberg G . Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature. 2014; 519(7542):242-6. PMC: 4447235. DOI: 10.1038/nature14115. View

Vannella K, Ramalingam T, Borthwick L, Barron L, Hart K, Thompson R . Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci Transl Med. 2016; 8(337):337ra65. DOI: 10.1126/scitranslmed.aaf1938. View

Lynch L, Hogan A, Duquette D, Lester C, Banks A, Leclair K . iNKT Cells Induce FGF21 for Thermogenesis and Are Required for Maximal Weight Loss in GLP1 Therapy. Cell Metab. 2016; 24(3):510-519. PMC: 5061124. DOI: 10.1016/j.cmet.2016.08.003. View

10.

Cipolletta D . Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. Immunology. 2014; 142(4):517-25. PMC: 4107662. DOI: 10.1111/imm.12262. View

11.

Schiering C, Krausgruber T, Chomka A, Frohlich A, Adelmann K, Wohlfert E . The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature. 2014; 513(7519):564-568. PMC: 4339042. DOI: 10.1038/nature13577. View

12.

Zuniga L, Shen W, Joyce-Shaikh B, Pyatnova E, Richards A, Thom C . IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol. 2010; 185(11):6947-59. PMC: 3001125. DOI: 10.4049/jimmunol.1001269. View

13.

Nussbaum J, Van Dyken S, von Moltke J, Cheng L, Mohapatra A, Molofsky A . Type 2 innate lymphoid cells control eosinophil homeostasis. Nature. 2013; 502(7470):245-8. PMC: 3795960. DOI: 10.1038/nature12526. View

14.

Odegaard J, Lee M, Sogawa Y, Bertholet A, Locksley R, Weinberg D . Perinatal Licensing of Thermogenesis by IL-33 and ST2. Cell. 2016; 166(4):841-854. PMC: 4985267. DOI: 10.1016/j.cell.2016.06.040. View

15.

Molofsky A, Van Gool F, Liang H, Van Dyken S, Nussbaum J, Lee J . Interleukin-33 and Interferon-γ Counter-Regulate Group 2 Innate Lymphoid Cell Activation during Immune Perturbation. Immunity. 2015; 43(1):161-74. PMC: 4512852. DOI: 10.1016/j.immuni.2015.05.019. View

16.

Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A . Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009; 15(8):930-9. PMC: 3115752. DOI: 10.1038/nm.2002. View

17.

Martin N, Martin M . Interleukin 33 is a guardian of barriers and a local alarmin. Nat Immunol. 2016; 17(2):122-31. DOI: 10.1038/ni.3370. View

18.

Hepworth M . Innate Lymphoid Cell Regulation: Meeting the Long-Lost Cousin. Trends Immunol. 2017; 38(12):873-874. DOI: 10.1016/j.it.2017.09.003. View

19.

Kolodin D, van Panhuys N, Li C, Magnuson A, Cipolletta D, Miller C . Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab. 2015; 21(4):543-57. PMC: 4747251. DOI: 10.1016/j.cmet.2015.03.005. View

20.

Trapnell C, Hendrickson D, Sauvageau M, Goff L, Rinn J, Pachter L . Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2012; 31(1):46-53. PMC: 3869392. DOI: 10.1038/nbt.2450. View