دورية أكاديمية
أعرض في EDS

Helminth-induced Th2 cell dysfunction is distinct from exhaustion and is maintained in the absence of antigen.

التفاصيل البيبلوغرافية
العنوان: Helminth-induced Th2 cell dysfunction is distinct from exhaustion and is maintained in the absence of antigen.
المؤلفون: Knipper JA; Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.; Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom., Ivens A; Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.; Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom., Taylor MD; Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.; Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
المصدر: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2019 Dec 09; Vol. 13 (12), pp. e0007908. Date of Electronic Publication: 2019 Dec 09 (Print Publication: 2019).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Public Library of Science Country of Publication: United States NLM ID: 101291488 Publication Model: eCollection Cited Medium: Internet ISSN: 1935-2735 (Electronic) Linking ISSN: 19352727 NLM ISO Abbreviation: PLoS Negl Trop Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: San Francisco, CA : Public Library of Science
مواضيع طبية MeSH: Antigens, Helminth/*immunology , Filariasis/*pathology , Filarioidea/*immunology , Th2 Cells/*immunology, Animals ; Disease Models, Animal ; Female ; Filariasis/immunology ; Gene Expression Profiling ; Mice, Inbred BALB C ; Phenotype ; Th2 Cells/pathology
مستخلص: T cell-intrinsic regulation, such as anergy, adaptive tolerance and exhaustion, is central to immune regulation. In contrast to Type 1 and Type 17 settings, knowledge of the intrinsic fate and function of Th2 cells in chronic Type 2 immune responses is lacking. We previously showed that Th2 cells develop a PD-1/PD-L2-dependent intrinsically hypo-responsive phenotype during infection with the filarial nematode Litomosoides sigmodontis, denoted by impaired functionality and parasite killing. This study aimed to elucidate the transcriptional changes underlying Th2 cell-intrinsic hypo-responsiveness, and whether it represents a unique and stable state of Th2 cell differentiation. We demonstrated that intrinsically hypo-responsive Th2 cells isolated from L. sigmodontis infected mice stably retained their dysfunctional Th2 phenotype upon transfer to naïve recipients, and had a divergent transcriptional profile to classical Th2 cells isolated prior to hypo-responsiveness and from mice exposed to acute Type 2 stimuli. Hypo-responsive Th2 cells displayed a distinct transcriptional profile to exhausted CD4+ T cells, but upregulated Blimp-1 and the anergy/regulatory-associated transcription factors Egr2 and c-Maf, and shared characteristics with tolerised T cells. Hypo-responsive Th2 cells increased mRNA expression of the soluble regulatory factors Fgl2, Cd38, Spp1, Areg, Metrnl, Lgals3, and Csf1, and a subset developed a T-bet+IFN-γ+ Th2/Th1 hybrid phenotype, indicating that they were not functionally inert. Contrasting with their lost ability to produce Th2 cytokines, hypo-responsive Th2 cells gained IL-21 production and IL-21R blockade enhanced resistance to L. sigmodontis. IL-21R blockade also increased the proportion of CD19+PNA+ germinal centre B cells and serum levels of parasite specific IgG1. This indicates a novel regulatory role for IL-21 during filarial infection, both in controlling protection and B cell responses. Thus, Th2 cell-intrinsic hypo-responsiveness is a distinct and stable state of Th2 cell differentiation associated with a switch from a classically active IL-4+IL-5+ Th2 phenotype, to a non-classical dysfunctional and potentially regulatory IL-21+Egr2+c-Maf+Blimp-1+IL-4loIL-5loT-bet+IFN-γ+ Th2 phenotype. This divergence towards alternate Th2 phenotypes during chronicity has broad implications for the outcomes and treatment of chronic Type 2-related infections and diseases.
Competing Interests: The authors have declared that no competing interests exist.
References: PLoS Pathog. 2013 Mar;9(3):e1003215. (PMID: 23516361)
Sci Immunol. 2016 Oct;1(5):null. (PMID: 28713870)
Lancet. 2001 Mar 10;357(9258):752-6. (PMID: 11253969)
Mol Immunol. 2013 Oct;55(3-4):283-91. (PMID: 23548837)
J Immunol. 2011 Feb 15;186(4):2472-81. (PMID: 21248253)
PLoS Negl Trop Dis. 2017 Jan 23;11(1):e0005307. (PMID: 28114324)
Front Immunol. 2017 Aug 21;8:1002. (PMID: 28871261)
Nat Immunol. 2013 Jun;14(6):603-10. (PMID: 23644506)
Genomics. 2010 Mar;95(3):138-42. (PMID: 20079422)
Immunity. 2014 Feb 20;40(2):289-302. (PMID: 24530057)
Nature. 2008 Sep 11;455(7210):246-50. (PMID: 18701887)
J Exp Med. 2012 Nov 19;209(12):2157-63. (PMID: 23129747)
J Clin Invest. 2009 Apr;119(4):1019-28. (PMID: 19258704)
Nature. 2006 Feb 9;439(7077):682-7. (PMID: 16382236)
J Immunol. 2009 Jul 15;183(2):797-801. (PMID: 19570826)
Trends Immunol. 2012 Apr;33(4):181-9. (PMID: 22398370)
J Immunol. 2005 Apr 15;174(8):4924-33. (PMID: 15814720)
Immunity. 2005 Oct;23(4):419-29. (PMID: 16226507)
Nat Immunol. 2011 Jun;12(6):492-9. (PMID: 21739672)
Biostatistics. 2003 Apr;4(2):249-64. (PMID: 12925520)
Infect Immun. 2003 Dec;71(12):6978-85. (PMID: 14638787)
Ann Parasitol Hum Comp. 1992;67(5):144-50. (PMID: 1295407)
Nat Rev Immunol. 2003 Sep;3(9):733-44. (PMID: 12949497)
J Allergy Clin Immunol. 2016 Sep;138(3):666-675. (PMID: 27476889)
Int Immunol. 2006 May;18(5):637-44. (PMID: 16608902)
Science. 2012 Feb 10;335(6069):723-7. (PMID: 22267581)
J Exp Med. 2009 May 11;206(5):991-9. (PMID: 19380637)
Annu Rev Immunol. 2003;21:305-34. (PMID: 12471050)
Immunity. 2001 Aug;15(2):303-11. (PMID: 11520464)
Trends Immunol. 2016 Aug;37(8):557-568. (PMID: 27389961)
J Immunol. 2006 Mar 1;176(5):3248-56. (PMID: 16493086)
Curr Opin Immunol. 2015 Jun;34:107-15. (PMID: 25801685)
Transplantation. 2014 Jun 27;97(12):1201-6. (PMID: 24717224)
Trends Immunol. 2014 Feb;35(2):51-60. (PMID: 24210163)
J Immunol. 2012 Jun 1;188(11):5478-88. (PMID: 22547705)
Nat Rev Immunol. 2015 Aug;15(8):486-99. (PMID: 26205583)
J Immunol. 2016 Jan 15;196(2):691-702. (PMID: 26667170)
Proc Natl Acad Sci U S A. 2014 Jul 29;111(30):E3081-90. (PMID: 25024218)
Nat Rev Immunol. 2010 Feb;10(2):80-1. (PMID: 20183893)
Elife. 2018 Jan 04;7:. (PMID: 29299998)
J Infect Dis. 1997 May;175(5):1276-80. (PMID: 9129104)
Eur J Immunol. 2016 May;46(5):1180-92. (PMID: 26931640)
PLoS Negl Trop Dis. 2015 May 08;9(5):e0003755. (PMID: 25955764)
Immunity. 2011 Jan 28;34(1):50-60. (PMID: 21236706)
PLoS Biol. 2013;11(8):e1001633. (PMID: 23976880)
J Clin Invest. 2000 Oct;106(8):1053-60. (PMID: 11032865)
Ann Rheum Dis. 2012 Apr;71 Suppl 2:i96-100. (PMID: 22460149)
Nat Immunol. 2015 Mar;16(3):267-75. (PMID: 25599562)
Nat Rev Immunol. 2011 Jun;11(6):375-88. (PMID: 21610741)
Nat Immunol. 2014 Dec;15(12):1116-25. (PMID: 25326751)
Nat Commun. 2014 Sep 03;5:4741. (PMID: 25182274)
J Exp Med. 2009 May 11;206(5):1001-7. (PMID: 19380638)
J Immunol. 2007 Aug 1;179(3):1431-7. (PMID: 17641008)
J Clin Invest. 2008 Apr;118(4):1311-21. (PMID: 18382743)
Immunol Rev. 2018 May;283(1):194-212. (PMID: 29664561)
معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; MR/K020196/1 United Kingdom MRC_ Medical Research Council; 095831 United Kingdom WT_ Wellcome Trust
المشرفين على المادة: 0 (Antigens, Helminth)
تواريخ الأحداث: Date Created: 20191210 Date Completed: 20200225 Latest Revision: 20210110
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6922449
DOI: 10.1371/journal.pntd.0007908
PMID: 31815932
قاعدة البيانات: MEDLINE
الوصف
تدمد:1935-2735
DOI:10.1371/journal.pntd.0007908