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: | Johanna A. Knipper, David Wright, Andrew P. Cope, Bernard Malissen, Rose Zamoyska |
| المصدر: | Frontiers in Immunology, Vol 11 (2020) |
| بيانات النشر: | Frontiers Media S.A., 2020. |
| سنة النشر: | 2020 |
| المجموعة: | LCC:Immunologic diseases. Allergy |
| مصطلحات موضوعية: | lymphopenia, PTPN22, autoimmunity, regulatory T cells, interleukin-7, Immunologic diseases. Allergy, RC581-607 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1664-3224 06254357 |
| العلاقة: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00052/fullTest; https://doaj.org/toc/1664-3224Test |
| DOI: | 10.3389/fimmu.2020.00052 |
| الوصول الحر: | https://doaj.org/article/06254357e70f4e06bdc855c88619687cTest |
| رقم الانضمام: | edsdoj.06254357e70f4e06bdc855c88619687c |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 16643224 06254357 |
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| DOI: | 10.3389/fimmu.2020.00052 |