Dataset Information

A Protective Role for NKG2D-H60a Interaction via Homotypic T Cell Contact in Nonobese Diabetic Autoimmune Diabetes Pathogenesis.

ABSTRACT: The NK group 2 member D (NKG2D) immune receptor is implicated in both human and mouse autoimmune diabetes. However, the significance of NKG2D in diabetes pathogenesis has been unclear due to conflicting reports as to the importance of this receptor in the NOD mouse model. In this study we demonstrate that NKG2D expression affects NOD diabetes development by at least two previously undescribed, and opposing, mechanisms. First, we demonstrate that the NKG2D ligand H60a is induced on activated NOD T cells, and that NKG2D-H60a interaction during CD8+ T cell differentiation into CTLs generally decreases the subsequent CTL effector cytokine response. This corresponds to an increase in diabetes development in NKG2D-deficient compared with wild-type NOD mice under microbiota-depleted conditions. Second, we demonstrate that NKG2D promotes NOD diabetes development through interaction with the microbiota. Together these findings reveal a previously undescribed role for NKG2D ligand expression by activated T cells in CTL development. Further, they demonstrate that NKG2D has both diabetogenic and antidiabetogenic roles in NOD diabetes development.

SUBMITTER: Trembath AP

PROVIDER: S-EPMC5828234 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A Protective Role for NKG2D-H60a Interaction via Homotypic T Cell Contact in Nonobese Diabetic Autoimmune Diabetes Pathogenesis.

Trembath Andrew P AP Sharma Neekun N Raju Saravanan S Polić Bojan B Markiewicz Mary A MA

ImmunoHorizons 20171107 9

The NK group 2 member D (NKG2D) immune receptor is implicated in both human and mouse autoimmune diabetes. However, the significance of NKG2D in diabetes pathogenesis has been unclear due to conflicting reports as to the importance of this receptor in the NOD mouse model. In this study we demonstrate that NKG2D expression affects NOD diabetes development by at least two previously undescribed, and opposing, mechanisms. First, we demonstrate that the NKG2D ligand H60a is induced on activated NOD ...[more]

PMID: 29497709

Similar Datasets

Project description:Background: Epigenetic alteration of the genome has been shown to provide palliative effects in mouse models of certain human autoimmune disorders. We have investigated whether chromatin remodeling could provide protection against autoimmune diabetes in nonobese diabetic (NOD) mice. Treatment of female mice during the transition from prediabetic to diabetic stage (18-24 weeks of age) with the well-characterized histone deacetylase inhibitor, Trichostatin A (TSA) effectively reduced the incidence of diabetes and abrogated the ability of splenocytes to adoptively transfer the disease into immunodeficient NOD.scid mice. Protection against diabetes was accompanied by histone hyperacetylation in pancreas and spleen, increased frequency of CD4+ CD62L+ cells in the spleen, reduction in cellular infiltration of islets, restoration of normoglycemia and glucose-induced insulin release by beta cells. In vitro activation of splenic T lymphocytes derived from protected mice resulted in enhanced expression of IFN-gamma mRNA and protein without altering the expression of Il4, Il17, Il18, Inos, and Tnfa genes nor the secretion of IL-2, IL-4, IL-17 and TNF-alpha proteins. Consistently, expression of the transcription factor involved in Ifng transcription, Tbet/Tbx21 but not Gata3 and Rorgt, respectively required for the transcription of Il4 and Il17, was upregulated in activated splenocytes of protected mice. These data indicate that abrogation of autoimmune diabetes is associated with the selective upregulation of certain inducible genes in T lymphocytes. Microarray analysis was performed to determine the changes in global gene expression underlying abrogation of autoimmune diabetes by TSA-mediated epigenetic modulation and identified a distinct group of genes down-regulated during this process. Female NOD mice were treated subcutaneously with TSA (500 µg/Kg body weight) during the transition from prediabetic to diabetic stage (18-24 weeks of age), at weekly intervals. Since we sought to determine the modulation of global gene expression associated with long-term protection against diabetes, TSA treated mice were killed between 32 and 36 weeks of age and total RNA was extracted from uninduced splenocytes. RNA was also extracted from splenocytes of untreated mice that became diabetic and those that did not develop diabetes till 36 weeks of age. Blood glucose levels were determined weekly to monitor the glycemic condition in untreated and TSA-treated mice. To minimize the variability in gene expression among individual mice, RNA was extracted from splenocytes of 3 to 5 mice per group and pooled. Each sample was hybridized to microchips in duplicate. Female NOD mice were treated with Trichostatin A (500 µg/Kg body weight) between 18-24 weeks of age or left untreated.

Project description:Type 1 diabetes (T1D) is a multigenic disease caused by T-cell mediated destruction of the insulin producing pancreatic islet ß-cells. The earliest sign of islet autoimmunity in NOD mice, islet leukocytic infiltration or insulitis, is obvious at around 5 weeks of age. The molecular alterations that occur in T cells prior to insulitis and that may contribute to T1D development are poorly understood. Since CD4 T-cells are essential to T1D development, we tested the hypothesis that multiple genes/molecular pathways are altered in these cells prior to insulitis. We performed a genome-wide transcriptome and pathway analysis of whole, untreated CD4 T-cells from 2, 3, and 4 week-old NOD mice in comparison to two control strains (NOR and C57BL/6). We identified many differentially expressed genes in the NOD mice at each time point. Many of these genes (herein referred to as NOD altered genes) lie within known diabetes susceptibility (insulin-dependent diabetes, Idd) regions, e.g. two diabetes resistant loci, Idd27 (tripartite motif-containing family genes) and Idd13 (several genes), and the CD4 T-cell diabetogenic activity locus, Idd9/11 (2 genes, KH domain containing, RNA binding, signal transduction associated 1 and protein tyrosine phosphatase 4a2). The biological processes associated with these altered genes included, apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks); inflammation and cell signaling/activation (predominant at 3 weeks); and innate and adaptive immune responses (predominant at 4 weeks). Pathway analysis identified several factors that may regulate these abnormalities: eight, common to all 3 ages (interferon regulatory factor 1, hepatic nuclear factor 4, alpha, transformation related protein 53, BCL2-like 1 (lies within Idd13), interferon gamma, interleukin 4, interleukin 15, and prostaglandin E2); and two each, common to 2 and 4 weeks (androgen receptor and interleukin 6); and to 3 and 4 weeks (interferon alpha and interferon regulatory factor 7). Others were unique to the various ages, e.g. myelocytomatosis oncogene, jun oncogene, and amyloid beta (A4) to 2 weeks; tumor necrosis factor, transforming growth factor, beta 1, NF?B, ERK, and p38MAPK to 3 weeks; and interleukin 12 and signal transducer and activator of transcription 4 to 4 weeks. Thus, our study demonstrated that expression of many genes that lie within several Idds (e.g. Idd27, Idd13 and Idd9/11) was altered in CD4 T-cells in the early induction phase of autoimmune diabetes and identified their associated molecular pathways. These data offer the opportunity to test hypotheses on the roles played by the altered genes/molecular pathways, to understand better the mechanisms of CD4 T-cell diabetogenesis, and to develop new therapeutic strategies for T1D.

Dataset Information

A Protective Role for NKG2D-H60a Interaction via Homotypic T Cell Contact in Nonobese Diabetic Autoimmune Diabetes Pathogenesis.

Publications

A Protective Role for NKG2D-H60a Interaction via Homotypic T Cell Contact in Nonobese Diabetic Autoimmune Diabetes Pathogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets