CD70 Inversely Regulates Regulatory T Cells and Invariant NKT Cells and Modulates Type 1 Diabetes in NOD Mice
| Autor: | Todd M. Brusko, Michael V. Wiles, David V. Serreze, Cheng Ye, Benjamin E. Low, John P. Driver |
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| Rok vydání: | 2020 |
| Předmět: |
T cell
Immunology Population chemical and pharmacologic phenomena Biology Lymphocyte Activation T-Lymphocytes Regulatory Article Immunomodulation Mice Mice Inbred NOD immune system diseases medicine Animals Humans Immunology and Allergy education NOD mice CD70 Mice Knockout education.field_of_study FOXP3 Cell Differentiation Forkhead Transcription Factors hemic and immune systems Natural killer T cell Phenotype Tumor Necrosis Factor Receptor Superfamily Member 7 Cell biology DNA-Binding Proteins Disease Models Animal Diabetes Mellitus Type 1 medicine.anatomical_structure Natural Killer T-Cells Homeostasis CD27 Ligand Signal Transduction Transcription Factors |
| Zdroj: | J Immunol |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The CD27–CD70 costimulatory pathway is essential for the full activation of T cells, but some studies show that blocking this pathway exacerbates certain autoimmune disorders. In this study, we report on the impact of CD27–CD70 signaling on disease progression in the NOD mouse model of type 1 diabetes (T1D). Specifically, our data demonstrate that CD70 ablation alters thymocyte selection and increases circulating T cell levels. CD27 signaling was particularly important for the thymic development and peripheral homeostasis of Foxp3+Helios+ regulatory T cells, which likely accounts for our finding that CD70-deficient NOD mice develop more-aggressive T1D onset. Interestingly, we found that CD27 signaling suppresses the thymic development and effector functions of T1D-protective invariant NKT cells. Thus, rather than providing costimulatory signals, the CD27–CD70 axis may represent a coinhibitory pathway for this immunoregulatory T cell population. Moreover, we showed that a CD27 agonist Ab reversed the effects of CD70 ablation, indicating that the phenotypes observed in CD70-deficient mice were likely due to a lack of CD27 signaling. Collectively, our results demonstrate that the CD27–CD70 costimulatory pathway regulates the differentiation program of multiple T cell subsets involved in T1D development and may be subject to therapeutic targeting. |
| Databáze: | OpenAIRE |
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