Abstract
CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here, we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in c-Jun N-terminal kinase 1 (JNK1) signaling prolongs islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM). Adoptively transferred JNK1-/- but not wild-type (WT) Tregs survive longer in the liver parenchyma of CDM. JNK1-/- Tregs are resistant to apoptosis and express anti-apoptotic molecules. JNK1-/- Tregs express higher levels of lymphocyte activation gene-3 molecule (LAG-3) on their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs. JNK1-/- Tregs inhibit liver alloimmune responses more efficiently than WT Tregs. JNK1-/- but not WT Tregs are able to inhibit IL-17 and IL-21 production through enhanced LAG-3 expression and IL-10 production. Our study identifies a novel role of JNK1 signaling in Tregs that enhances islet allograft survival in the liver parenchyma of CDM.
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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Allografts / immunology
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Allografts / transplantation
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Animals
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Antigens, CD / genetics
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Diabetes Mellitus, Experimental / immunology*
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Diabetes Mellitus, Experimental / pathology
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Diabetes Mellitus, Experimental / therapy
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Forkhead Transcription Factors / genetics
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Gene Expression Regulation / immunology
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Graft Survival / genetics
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Graft Survival / immunology*
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Humans
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Interleukin-17 / genetics
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Interleukin-2 Receptor alpha Subunit / genetics
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Interleukin-2 Receptor alpha Subunit / immunology
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Interleukins / genetics
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Lymphocyte Activation Gene 3 Protein
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Mice
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Mice, Inbred NOD
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Mitogen-Activated Protein Kinase 8 / genetics*
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Mitogen-Activated Protein Kinase 8 / immunology
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T-Lymphocytes, Regulatory / immunology
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Transplantation Tolerance / immunology*
Substances
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Antigens, CD
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-17
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Interleukin-2 Receptor alpha Subunit
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Interleukins
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Mitogen-Activated Protein Kinase 8
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interleukin-21
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Lymphocyte Activation Gene 3 Protein