The Biology of Autoimmune Response in the Scurfy Mice That Lack the CD4+Foxp3+ Regulatory T-Cells

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2014 May 17

PMID 24832045

Citations 11

Authors

Shyr-Te Ju

Rahul Sharma

Felicia Gaskin

John T Kung

Shu Man Fu

Affiliations

Soon will be listed here.

Abstract

Due to a mutation in the Foxp3 transcription factor, Scurfy mice lack regulatory T-cells that maintain self-tolerance of the immune system. They develop multi-organ inflammation (MOI) and die around four weeks old. The affected organs are skin, tail, lungs and liver. In humans, endocrine and gastrointestinal inflammation are also observed, hence the disease is termed IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. The three week period of fatal MOI offers a useful autoimmune model in which the controls by genetics, T-cell subsets, cytokines, and effector mechanisms could be efficiently investigated. In this report, we will review published work, summarize our recent studies of Scurfy double mutants lacking specific autoimmune-related genes, discuss the cellular and cytokine controls by these genes on MOI, the organ-specificities of the MOI controlled by environments, and the effector mechanisms regulated by specific Th cytokines, including several newly identified control mechanisms for organ-specific autoimmune response.

Citing Articles

IL-27 Gene Therapy Ameliorates IPEX Syndrome Caused by Germline Mutation of Foxp3 Gene: A Major Role for Induction of IL-10.

Liu J, Jabbari A, Lin C, Akkanapally V, Frankel W, Basu S J Immunol. 2024; 213(5):559-566.

PMID: 38975727 PMC: 11333164. DOI: 10.4049/jimmunol.2400056.

HELIOS-expressing human CD8 T cells exhibit limited effector functions.

Neyens D, Hirsch T, Abdel Aziz Issa Abdel Hadi A, Dauguet N, Vanhaver C, Bayard A Front Immunol. 2024; 14:1308539.

PMID: 38187391 PMC: 10770868. DOI: 10.3389/fimmu.2023.1308539.

Steroid receptor coactivator 3 is a key modulator of regulatory T cell-mediated tumor evasion.

Han S, Jain P, Gilad Y, Xia Y, Sung N, Park M Proc Natl Acad Sci U S A. 2023; 120(23):e2221707120.

PMID: 37253006 PMC: 10266015. DOI: 10.1073/pnas.2221707120.

Antibiotic-modulated microbiome suppresses lethal inflammation and prolongs lifespan in Treg-deficient mice.

He B, Liu Y, Hoang T, Tian X, Taylor C, Luo M Microbiome. 2019; 7(1):145.

PMID: 31699146 PMC: 6839243. DOI: 10.1186/s40168-019-0751-1.

MALT1-Deficient Mice Develop Atopic-Like Dermatitis Upon Aging.

Demeyer A, Nuffel E, Baudelet G, Driege Y, Kreike M, Muyllaert D Front Immunol. 2019; 10:2330.

PMID: 31632405 PMC: 6779721. DOI: 10.3389/fimmu.2019.02330.

References

Heath W, Carbone F, Bertolino P, Kelly J, Cose S, Miller J . Expression of two T cell receptor alpha chains on the surface of normal murine T cells. Eur J Immunol. 1995; 25(6):1617-23. DOI: 10.1002/eji.1830250622. View

Randolph D, Stephens R, Carruthers C, Chaplin D . Cooperation between Th1 and Th2 cells in a murine model of eosinophilic airway inflammation. J Clin Invest. 1999; 104(8):1021-9. PMC: 408580. DOI: 10.1172/JCI7631. View

Alard P, Thompson C, Agersborg S, Thatte J, Setiady Y, Samy E . Endogenous oocyte antigens are required for rapid induction and progression of autoimmune ovarian disease following day-3 thymectomy. J Immunol. 2001; 166(7):4363-9. DOI: 10.4049/jimmunol.166.7.4363. View

Lin W, Truong N, Grossman W, Haribhai D, Williams C, Wang J . Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol. 2005; 116(5):1106-15. DOI: 10.1016/j.jaci.2005.08.046. View

Chen Z, Benoist C, Mathis D . How defects in central tolerance impinge on a deficiency in regulatory T cells. Proc Natl Acad Sci U S A. 2005; 102(41):14735-40. PMC: 1253589. DOI: 10.1073/pnas.0507014102. View

Godfrey V, Rouse B, Wilkinson J . Transplantation of T cell-mediated, lymphoreticular disease from the scurfy (sf) mouse. Am J Pathol. 1994; 145(2):281-6. PMC: 1887402. View

Sharma R, Jarjour W, Zheng L, Gaskin F, Fu S, Ju S . Large functional repertoire of regulatory T-cell suppressible autoimmune T cells in scurfy mice. J Autoimmun. 2007; 29(1):10-9. PMC: 2099300. DOI: 10.1016/j.jaut.2007.04.001. View

Blair P, Bultman S, Haas J, Rouse B, Wilkinson J, Godfrey V . CD4+CD8- T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J Immunol. 1994; 153(8):3764-74. View

Pacholczyk R, Kern J, Singh N, Iwashima M, Kraj P, Ignatowicz L . Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells. Immunity. 2007; 27(3):493-504. PMC: 2276657. DOI: 10.1016/j.immuni.2007.07.019. View

10.

Sharma R, Sung S, Abaya C, Ju A, Fu S, Ju S . IL-2 regulates CD103 expression on CD4+ T cells in Scurfy mice that display both CD103-dependent and independent inflammation. J Immunol. 2009; 183(2):1065-73. PMC: 2734909. DOI: 10.4049/jimmunol.0804354. View

11.

Rubtsov Y, Rasmussen J, Chi E, Fontenot J, Castelli L, Ye X . Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008; 28(4):546-58. DOI: 10.1016/j.immuni.2008.02.017. View

12.

Sharma R, Ju A, Kung J, Fu S, Ju S . Rapid and selective expansion of nonclonotypic T cells in regulatory T cell-deficient, foreign antigen-specific TCR-transgenic scurfy mice: antigen-dependent expansion and TCR analysis. J Immunol. 2008; 181(10):6934-41. PMC: 2734502. DOI: 10.4049/jimmunol.181.10.6934. View

13.

Zheng L, Sharma R, Gaskin F, Fu S, Ju S . A novel role of IL-2 in organ-specific autoimmune inflammation beyond regulatory T cell checkpoint: both IL-2 knockout and Fas mutation prolong lifespan of Scurfy mice but by different mechanisms. J Immunol. 2007; 179(12):8035-41. PMC: 3527098. DOI: 10.4049/jimmunol.179.12.8035. View

14.

Sharma R, Zheng L, Deshmukh U, Jarjour W, Sung S, Fu S . A regulatory T cell-dependent novel function of CD25 (IL-2Ralpha) controlling memory CD8(+) T cell homeostasis. J Immunol. 2007; 178(3):1251-5. DOI: 10.4049/jimmunol.178.3.1251. View

15.

Cole K, Strick C, Paradis T, Ogborne K, Loetscher M, Gladue R . Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med. 1998; 187(12):2009-21. PMC: 2212354. DOI: 10.1084/jem.187.12.2009. View

16.

Medoff B, Thomas S, Luster A . T cell trafficking in allergic asthma: the ins and outs. Annu Rev Immunol. 2008; 26:205-32. DOI: 10.1146/annurev.immunol.26.021607.090312. View

17.

Hansen G, Berry G, DeKruyff R, Umetsu D . Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest. 1999; 103(2):175-83. PMC: 407883. DOI: 10.1172/JCI5155. View

18.

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

19.

Sharma R, Sung S, Gaskin F, Fu S, Ju S . A novel function of IL-2: chemokine/chemoattractant/retention receptor genes induction in Th subsets for skin and lung inflammation. J Autoimmun. 2012; 38(4):322-31. PMC: 3358580. DOI: 10.1016/j.jaut.2012.02.001. View

20.

Chen Z, Herman A, Matos M, Mathis D, Benoist C . Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med. 2005; 202(10):1387-97. PMC: 2212985. DOI: 10.1084/jem.20051409. View