C-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong islet allograft survival in diabetic mice

Deepak Tripathi,Satyanarayana S Cheekatla,Elwyn Welch,Ramya Sivangala Thandi,Amy R Tvinnereim,Padmaja Paidipally,Rajesh Kumar Radhakrishnan,Ramakrishna Vankayalapati

doi:10.1038/s41598-018-21477-9

Deepak Tripathi, Satyanarayana S Cheekatla + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-21477-9

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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.

Highlights

On their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs
We found that transplantation of allogeneic pancreatic islets along with Tregs defective in Jun N-terminal kinase 1 (JNK1) signaling prolonged islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM)
We found that adoptively transferred JNK1−/− Tregs were less apoptotic and persisted for a longer period of time in the transplanted liver compared with WT Tregs

Summary

Introduction

On their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs. Our study identifies a novel role of JNK1 signaling in Tregs that enhances islet allograft survival in the liver parenchyma of CDM. Tregs express transcription factors such as retinoid-related orphan receptor γ (RORγ), and inflammatory cytokines can inhibit their immunosuppressive capacity and induce Th17 cytokine production[10,11,12]. This finding suggests that it is important to modify Tregs to increase their survival and immunosuppressive potential before using them for immunosuppressive therapies. In the current study, using an islet allograft transplantation model, we determined that JNK1-defective Tregs prolong islet allograft survival in liver parenchyma more efficiently than wild-type (WT) Tregs. We found that JNK1-defective Tregs inhibit IL-17 and IL-21-mediated inflammation through the production of IL-10 and expression of LAG (lymphocyte activation gene) -3

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