Abstract
Signaling through IL-2/IL-15Rβ (CD122) is essential for the differentiation and function of T cells and NK cells. A mAb against CD122 has been implicated to suppress autoimmune type 1 diabetes (T1D) development in animal models. However, the mechanisms remain poorly understood. We find that in vivo administration of an anti-CD122 mAb (CD122 blockade) restores immune tolerance in nonobese diabetic (NOD) mice via multiple mechanisms. First, CD122 blockade selectively ablates pathogenic NK cells and memory phenotype CD8+ T cells from pancreatic islets. In contrast, islet CD4+Foxp3+ Tregs are only mildly affected. Second, CD122 blockade suppresses IFN-γ production in islet immune cells. Third, CD122 blockade inhibits the conversion of islet Th17 cells into diabetogenic Th1 cells. Furthermore, a combination of anti-CD122 mAb and Treg-trophic cytokines (IL-2 or IL-33) enhances the abundance and function of islet Tregs. In summary, these data provide crucial mechanistic insights into CD122 blockade-mediated immunoregulation and support therapeutic benefits of this combinational treatment in T1D.
Keywords:
Autoimmunity; Cytokines; Diabetes; Inflammation; NK cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage*
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / isolation & purification
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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Diabetes Mellitus, Type 1 / drug therapy*
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Diabetes Mellitus, Type 1 / immunology
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Disease Models, Animal
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Drug Therapy, Combination / methods
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Female
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Hybridomas
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Immune Tolerance / drug effects*
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Immunologic Factors / administration & dosage*
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Interleukin-2 / administration & dosage
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Interleukin-2 Receptor beta Subunit / antagonists & inhibitors*
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Interleukin-2 Receptor beta Subunit / immunology
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Interleukin-33 / administration & dosage
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Islets of Langerhans / cytology
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Islets of Langerhans / immunology
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Mice
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Mice, Inbred NOD
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / administration & dosage
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Th17 Cells / drug effects
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Th17 Cells / immunology
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Treatment Outcome
Substances
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Antibodies, Monoclonal
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IL2 protein, human
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IL33 protein, human
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Il2rb protein, mouse
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Immunologic Factors
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Interleukin-2
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Interleukin-2 Receptor beta Subunit
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Interleukin-33
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Recombinant Proteins