دورية أكاديمية
Helminth-induced Th2 cell dysfunction is distinct from exhaustion and is maintained in the absence of antigen.
العنوان: | Helminth-induced Th2 cell dysfunction is distinct from exhaustion and is maintained in the absence of antigen. |
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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. |
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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 |
تدمد: | 1935-2735 |
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DOI: | 10.1371/journal.pntd.0007908 |