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

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.

JNK signaling in cancer cell survival

“…JNK1 activation is required for erythropoietin‐mediated cell survival through the inactivation of Bcl‐associated death protein . JNK1 also plays a role in gastric cancer cell survival and promotes islet allograft survival in diabetic mice …”

“…23 JNK1 also plays a role in gastric cancer cell survival and promotes islet allograft survival in diabetic mice. 20,46 JNK exerts a prosurvival effect by modulating cancer cell proliferation, 50-52 it promotes human pancreatic cancer cell proliferation by regulating microRNA-92a and glucose-regulated protein 78 (GRP78). 53,54 Cancerous inhibitor of PP2A (CIP2A) is an oncoprotein that promotes cancer cell proliferation; moreover, CIP2A overexpression in lung cancer promotes lung cancer cell proliferation, 55 and CIP2A activation affects the phosphorylation of JNK and MKK4/MKK4.…”

Regulatory T Cell Therapy Following Liver Transplantation

“…Deleting the gene‐encoding c‐Jun N‐terminal kinase 1 (JNK1) in Tregs was shown to make them resistant to apoptosis. ( 113 ) JNK1 −/− Tregs significantly survived much longer than wildtype Tregs, showing an 11‐fold difference in number after 4 months of follow‐up. Moreover, JNK1 −/− Tregs produced more IL10 and TGF‐β and effectively inhibited interleukin 17–mediated and interleukin 21–mediated inflammatory responses.…”

“…Moreover, JNK1 −/− Tregs produced more IL10 and TGF‐β and effectively inhibited interleukin 17–mediated and interleukin 21–mediated inflammatory responses. ( 113 ) As discussed previously, Tregs can also acquire a proinflammatory phenotype under some conditions, ( 74,79,98 ) a process that is dependent on the activation of protein kinase C‐θ (PKC‐θ). In 1 preclinical study, using CRISPR‐Cas9 to delete the PRKCQ gene, which encodes for PKC‐θ, reduced transdifferentiation of Tregs into T helper 17 (Th17) cells and maintained their stability and suppressive function.…”

BCG vaccination reduces the mortality of Mycobacterium tuberculosis–infected type 2 diabetes mellitus mice

“…Single-cell suspensions of mouse lungs and spleen cells were prepared from all the groups of mice. CD4 + CD25 + Tregs were isolated by magnetic beads according to the manufacturer's instructions (Miltenyi Biotec) and as described previously (84). Isolated cells contained > 97% CD4 + CD25 + Foxp3 + cells, as measured by flow cytometry.…”