γδ T Cells Protect the Liver and Lungs of Mice from Autoimmunity Induced by Scurfy Lymphocytes

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2016 Jan 17

PMID 26773142

Citations 13

Authors

Hideyuki Ujiie

Ethan M Shevach

Affiliations

Soon will be listed here.

Abstract

γδ T cells have been shown to have immunoregulatory functions in several experimental autoimmune models. A mutation of the Foxp3 gene leads to the absence of regulatory T cells (Tregs) and a fatal systemic autoimmune disease in scurfy mice. Transfer of scurfy lymphocytes to RAG deficient (RAG(-/-)) recipients reproduces the inflammatory phenotype of the scurfy donor, including hepatitis and pneumonitis. In this study, we show that TCRα(-/-) recipients, which lack αβ T cells but have γδ T cells and B cells, are significantly protected from the hepatitis and pneumonitis, but not the dermatitis, induced by adoptive transfer of scurfy lymphocytes. Cotransfer of γδ T cells, but not B cells, prevented hepatitis and pneumonitis in RAG(-/-) recipients of scurfy lymphocytes. γδ T cells in the TCRα(-/-) recipients of scurfy cells markedly expanded and expressed a highly activated (CD62L(lo)CD44(hi)) phenotype. The activated γδ T cells expressed high levels of CD39 and NKG2D on their cell surface. A high frequency of scurfy T cells in TCRα(-/-) recipients produced IL-10, suggesting that γδ T cells may enhance suppressor cytokine production from scurfy T cells in TCRα(-/-) recipients. This study indicates that γδ T cells may contribute to the maintenance of immunological homeostasis by suppressing autoreactive T cells in liver and lung.

Citing Articles

Lkb1 orchestrates γδ T-cell metabolic and functional fitness to control IL-17-mediated autoimmune hepatitis.

Xiao Z, Wang S, Luo L, Lv W, Feng P, Sun Y Cell Mol Immunol. 2024; 21(6):546-560.

PMID: 38641698 PMC: 11143210. DOI: 10.1038/s41423-024-01163-9.

Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers.

Becker S, Petrich B, Yu B, Knight K, Brown H, Raikar S Mol Ther Oncolytics. 2023; 29:145-157.

PMID: 37387794 PMC: 10300408. DOI: 10.1016/j.omto.2023.05.007.

TOX deficiency facilitates the differentiation of IL-17A-producing γδ T cells to drive autoimmune hepatitis.

He Q, Lu Y, Tian W, Jiang R, Yu W, Liu Y Cell Mol Immunol. 2022; 19(10):1102-1116.

PMID: 35986136 PMC: 9508111. DOI: 10.1038/s41423-022-00912-y.

Role of the Gastric Microbiome in Gastric Cancer: From Carcinogenesis to Treatment.

Yang J, Zhou X, Liu X, Ling Z, Ji F Front Microbiol. 2021; 12:641322.

PMID: 33790881 PMC: 8005548. DOI: 10.3389/fmicb.2021.641322.

Ectonucleotidase Modulation of Lymphocyte Function in Gut and Liver.

Savio L, Robson S, Longhi M Front Cell Dev Biol. 2021; 8:621760.

PMID: 33553158 PMC: 7859358. DOI: 10.3389/fcell.2020.621760.

References

Kabelitz D, Peters C, Wesch D, Oberg H . Regulatory functions of γδ T cells. Int Immunopharmacol. 2013; 16(3):382-7. DOI: 10.1016/j.intimp.2013.01.022. View

He W, Hao J, Dong S, Gao Y, Tao J, Chi H . Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin. J Immunol. 2010; 185(1):126-33. PMC: 3813958. DOI: 10.4049/jimmunol.0903767. View

Aschermann S, Lehmann C, Mihai S, Schett G, Dudziak D, Nimmerjahn F . B cells are critical for autoimmune pathology in Scurfy mice. Proc Natl Acad Sci U S A. 2013; 110(47):19042-7. PMC: 3839754. DOI: 10.1073/pnas.1313547110. View

Otsuka A, Hanakawa S, Miyachi Y, Kabashima K . CD39: a new surface marker of mouse regulatory γδ T cells. J Allergy Clin Immunol. 2013; 132(6):1448-51. DOI: 10.1016/j.jaci.2013.05.037. View

Candando K, Lykken J, Tedder T . B10 cell regulation of health and disease. Immunol Rev. 2014; 259(1):259-72. PMC: 4049540. DOI: 10.1111/imr.12176. View

Mayer C, Tian L, Hesse C, Kuhl A, Swallow M, Kruse F . Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals. J Autoimmun. 2013; 50:23-32. DOI: 10.1016/j.jaut.2013.08.010. View

Sun X, Wu Y, Gao W, Enjyoji K, Csizmadia E, Muller C . CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology. 2010; 139(3):1030-40. PMC: 2930043. DOI: 10.1053/j.gastro.2010.05.007. View

Collison L, Chaturvedi V, Henderson A, Giacomin P, Guy C, Bankoti J . IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010; 11(12):1093-101. PMC: 3008395. DOI: 10.1038/ni.1952. View

Sharma R, Sharma P, Kim Y, Leitinger N, Lee J, Fu S . IL-2-controlled expression of multiple T cell trafficking genes and Th2 cytokines in the regulatory T cell-deficient scurfy mice: implication to multiorgan inflammation and control of skin and lung inflammation. J Immunol. 2010; 186(2):1268-78. PMC: 3136806. DOI: 10.4049/jimmunol.1002677. View

10.

Hao J, Dong S, Xia S, He W, Jia H, Zhang S . Regulatory role of Vγ1 γδ T cells in tumor immunity through IL-4 production. J Immunol. 2011; 187(10):4979-86. DOI: 10.4049/jimmunol.1101389. View

11.

Zhao N, Hao J, Ni Y, Luo W, Liang R, Cao G . Vγ4 γδ T cell-derived IL-17A negatively regulates NKT cell function in Con A-induced fulminant hepatitis. J Immunol. 2011; 187(10):5007-14. DOI: 10.4049/jimmunol.1101315. View

12.

Strid J, Sobolev O, Zafirova B, Polic B, Hayday A . The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science. 2011; 334(6060):1293-7. PMC: 3842529. DOI: 10.1126/science.1211250. View

13.

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

14.

Antonioli L, Pacher P, Vizi E, Hasko G . CD39 and CD73 in immunity and inflammation. Trends Mol Med. 2013; 19(6):355-67. PMC: 3674206. DOI: 10.1016/j.molmed.2013.03.005. View

15.

Drobyski W, Klein J . Adoptively transferred gamma delta T cells indirectly regulate murine graft-versus-host reactivity following donor leukocyte infusion therapy in mice. J Immunol. 2000; 165(3):1634-40. DOI: 10.4049/jimmunol.165.3.1634. View

16.

Wildin R, Ramsdell F, Peake J, Faravelli F, Casanova J, Buist N . X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001; 27(1):18-20. DOI: 10.1038/83707. View

17.

Bennett C, Christie J, Ramsdell F, Brunkow M, Ferguson P, Whitesell L . The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001; 27(1):20-1. DOI: 10.1038/83713. View

18.

Brunkow M, Jeffery E, Hjerrild K, Paeper B, Clark L, Yasayko S . Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001; 27(1):68-73. DOI: 10.1038/83784. View

19.

Ohta A, Sitkovsky M . Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature. 2002; 414(6866):916-20. DOI: 10.1038/414916a. View

20.

Nagaeva O, Jonsson L, Mincheva-Nilsson L . Dominant IL-10 and TGF-beta mRNA expression in gammadeltaT cells of human early pregnancy decidua suggests immunoregulatory potential. Am J Reprod Immunol. 2002; 48(1):9-17. DOI: 10.1034/j.1600-0897.2002.01131.x. View