Title: Generation of a nitric oxide signaling pathway in mesenchymal stem cells promotes endothelial lineage commitment
Authors: Bandara, N
Gurusinghe, S
Kong, A
Mitchell, G
Wang, LX
Lim, SY
Strappe, P
Issue Year: 2019
Publisher WILEY
Abstract In type 1 diabetes, maturation of activated autoreactive CD8(+) T cells to fully armed effector cytotoxic T lymphocytes (CTL) occurs within the islet. At present the signals required for the maturation process are poorly defined. Cytokines could potentially provide the necessary third signal required to generate fully mature CTL capable of killing insulin-producing beta-cells. To determine whether autoreactive CTL within islets respond to cytokines we generated non-obese diabetic (NOD) mice with a reporter for cytokine signalling. These mice express a reporter gene, hCD4, under the control of the endogenous regulatory elements for suppressor of cytokine signalling (SOCS)1, which is itself regulated by pro-inflammatory cytokines. In NOD mice, the hCD4 reporter was expressed in infiltrated islets and the expression level was positively correlated with the frequency of infiltrating CD45(+) cells. SOCS1 reporter expression was induced in transferred beta-cell-specific CD8(+) 8.3T cells upon migration from pancreatic draining lymph nodes into islets. To determine which cytokines induced SOCS1 promoter activity in islets, we examined hCD4 reporter expression and CTL maturation in the absence of the cytokine receptors IFNAR1 or IL-21R. We show that IFNAR1 deficiency does not confer protection from diabetes in 8.3 TCR transgenic mice, nor is IFNAR1 signalling required for SOCS1 reporter upregulation or CTL maturation in islets. In contrast, IL-21R-deficient 8.3 mice have reduced diabetes incidence and reduced SOCS1 reporter activity in islet CTLs. However IL-21R deficiency did not affect islet CD8(+) T cell proliferation or expression of granzyme B or IFN gamma. Together these data indicate that autoreactive CD8(+) T cells respond to IL-21 and not type I IFNs in the islets of NOD mice, but neither IFNAR1 nor IL-21R are required for islet intrinsic CTL maturation.
URI: https://publications.svi.edu.au/publications/7630
Other Identifiers 10.1002/jcp.28640
Publication type Article