دورية أكاديمية
PTPN22 Acts in a Cell Intrinsic Manner to Restrict the Proliferation and Differentiation of T Cells Following Antibody Lymphodepletion.
| العنوان: | PTPN22 Acts in a Cell Intrinsic Manner to Restrict the Proliferation and Differentiation of T Cells Following Antibody Lymphodepletion. |
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| المؤلفون: | Knipper JA; Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom., Wright D; Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom., Cope AP; Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom., Malissen B; Centre d'Immunologie de Marseille-Luminy, INSERM, CNRS, Aix Marseille Université, Marseille, France.; Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS UMR, Marseille, France., Zamoyska R; Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom. |
| المصدر: | Frontiers in immunology [Front Immunol] 2020 Jan 28; Vol. 11, pp. 52. Date of Electronic Publication: 2020 Jan 28 (Print Publication: 2020). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Lausanne : Frontiers Research Foundation] |
| مواضيع طبية MeSH: | Autoimmune Diseases/*immunology , Lymphopenia/*immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 22/*immunology , T-Lymphocytes, Regulatory/*immunology , T-Lymphocytes, Regulatory/*metabolism, Animals ; Antibodies ; Autoimmunity/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Female ; Forkhead Transcription Factors/metabolism ; Lymphocyte Depletion ; Lymphopenia/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism |
| مستخلص: | Lymphopenic insult has been shown to precipitate the initiation of autoimmune disease in murine models such as the Non-obese diabetic mouse. Similarly, in man lymphopenia induced by mAb therapy, for instance Alemtuzumab as treatment for Multiple Sclerosis, can precipitate development of secondary autoimmune disease in up to 30 % of patients. We asked whether an identified autoimmune susceptibility locus might increase the risk of developing autoimmunity in the context of mAb-induced lymphopenia in a mouse model. A single nucleotide polymorphism (SNP) in the gene encoding the tyrosine phosphatase PTPN22 (R620W) is associated with multiple human autoimmune diseases, and PTPN22 has been shown to modulate T cell responses, particularly to weak antigens. In keeping with this, PTPN22-deficient or PTPN22 R619W mutant murine T cells adoptively transferred into immunodeficient lymphopenic hosts showed a higher lymphopenia-induced proliferation rate than WT cells. We induced lymphopenia by treating wild-type or PTPN22 knock-out mice with T cell depleting antibodies and monitored reconstitution of the T cell pool. We found that PTPN22 deficient T cells acquired a more activated effector phenotype, with significantly more IFNγ producing cells. This resulted from expansion driven by self-peptide MHC, as it was evident when the contribution of IL-7 to lymphopenic expansion was blocked with IL-7R Ab. Interestingly, Foxp3 + Tregs were also considerably expanded in PTPN22-deficient and PTPN22 R619W mice, as was the frequency of both CD25 + and CD25 - CD4 T cells that produce IL-10. Using bone marrow chimeric mice, we showed that PTPN22 influenced development of both regulatory and effector T cell functions in a cell-intrinsic manner. Overall the expansion of Tregs is likely to keep the expanded T effector populations in check and sparing Treg during therapeutic mAb depletion may be a useful strategy to prevent occurrence of secondary autoimmunity. (Copyright © 2020 Knipper, Wright, Cope, Malissen and Zamoyska.) |
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| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; 205014/Z/16/Z United Kingdom WT_ Wellcome Trust; WT205014/Z/16/Z United Kingdom WT_ Wellcome Trust; 20525 United Kingdom VAC_ Versus Arthritis |
| فهرسة مساهمة: | Keywords: PTPN22; autoimmunity; interleukin-7; lymphopenia; regulatory T cells |
| المشرفين على المادة: | 0 (Antibodies) 0 (Forkhead Transcription Factors) 0 (Foxp3 protein, mouse) EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 22) EC 3.1.3.48 (Ptpn22 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20200213 Date Completed: 20210303 Latest Revision: 20230315 |
| رمز التحديث: | 20230315 |
| مُعرف محوري في PubMed: | PMC6997546 |
| DOI: | 10.3389/fimmu.2020.00052 |
| PMID: | 32047502 |
| قاعدة البيانات: | MEDLINE |
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