| Summary: | 碩士 === 國防醫學院 === 微生物及免疫學研究所 === 106 === Non-obese diabetic (NOD) mice are a well-established murine model which mimics T cell-mediated autoimmune diabetes in human. In the initiation of disease, conventional dendritic cells (cDCs) present autoantigens to prime diabetogenic T cells. These autoreactive T cells infiltrate into pancreatic islets and cause severe destruction of beta cells. Insufficient to produce insulin, hosts develop diabetes results from hyperglycemia.
X-box protein 1 (XBP1) is a transcription factor. Under endoplasmic reticulum stress (ER stress), spliced form Xbp1 (Xbp1s) is generated. Xbp1s can induce unfolded proteins response (UPR) pathways and help cells to solve these difficulties. It has been found that Xbp1 is crucial to the development of dendritic cells (DCs) and that XBP1-deficient DCs had lower viability after stimulated by TLR agonists. Otherwise, specific deletion of Xbp1 in DCs promote activation of regulated Ire1-dependent decay (RIDD) signalings and finally curtailed the capacity of cross-presentation in CD8alpha+ subset of DCs. In 2015, a research discovered high expression of XBP1s in DCs from tumor parts. In this case, Xbp1-deficient DCs extended the survival of ovarian cancer-bearing mice by promoting anti-tumor responses including proliferation and IFN-gamma production of effector T cells. Collectively, XBP1 plays a regulatory role of development and functions, especially for T cell priming, in DCs.
In this study, we aim to investigate the role of Xbp1 in DCs during the development of autoimmune diabetes. We observed the transcriptional level of Xbp1s in CD8alpha+ DC subset from spleens of NOD mice is even less than that of B6 mice. On the other hand, the expression of Xbp1s in splenic CD8alpha+ DCs was comparable between NOD and NOD.Rag1-/- mice. Moreover, expression of Xbp1s in DC subsets from different ages of B6 mice increased with their ages. However, the trend of Xbp1s expression in DCs from NOD mice was inconsistent. These findings indicate that despite the sequence of Xbp1 in B6 and NOD mice are identical, DCs of NOD mice are defective to generate Xbp1s.
Since we assumed that DCs which are closer to pancreata are more diabetogenic, we compare expression of Xbp1 in DCs from spleens or pancreatic lymph nodes (PLNs) or pancreata. We found that expression of Xbp1s in pancreatic DCs was lower than those in DCs from spleens or PLNs. To check whether DCs of NOD mice lack a suitable inducer to generate Xbp1s, we detect a potential factor – reactive oxygen species (ROS) — which has been identified as an inducer of XBP1s to DCs in the tumor microenvironment. Our results displayed that ROS levels in DCs increased from spleens to PLNs and pancreata in NOD mice. This indicates that autoimmune lesions trigger the production of ROS but do not arise expression of Xbp1s in DCs of NOD mice. In sum, our results imply that deficient expression of Xbp1s in NOD DCs via ROS-mediated signaling may enhance functions of DCs to effectively prime autoreactive T cells.
In the future, we will further dissect the underlying mechanisms of less expression of Xbp1s in DCs of NOD mice. Moreover, we will also investigate whether overexpression of Xbp1s in DCs of NOD mice could weaken the diabetogenicities of T cells and attenuate the development of autoimmune diabetes in NOD mice.
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