Differentiating MHC-Dependent and -Independent Mechanisms of Lymph Node Stromal Cell Regulation of Proinsulin-Specific CD8+ T Cells in Type 1 Diabetes.
Terri C ThayerJoanne DaviesJames A PearsonStephanie J HannaWen LiFlorence Susan WongPublished in: Diabetes (2020)
Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8+ T cells, escaping central and peripheral tolerance, contribute to β-cell destruction. Using G9Cα-/-CD8+ T cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the NOD mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα-/-CD8+ T-cell cytotoxicity and dendritic cell-induced proliferation, they failed to sufficiently regulate T cells stimulated by anti-CD3/CD28. In contrast, non-MHC-matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.
Keyphrases
- type diabetes
- lymph node
- induced apoptosis
- dendritic cells
- cell cycle arrest
- glycemic control
- mouse model
- single cell
- cardiovascular disease
- regulatory t cells
- neoadjuvant chemotherapy
- cell therapy
- signaling pathway
- magnetic resonance
- endoplasmic reticulum stress
- cell death
- computed tomography
- metabolic syndrome
- squamous cell carcinoma
- magnetic resonance imaging
- contrast enhanced
- immune response
- adipose tissue
- weight loss
- drug induced
- radiation therapy
- mesenchymal stem cells
- cell proliferation
- skeletal muscle