Loss of MafA and MafB expression promotes islet inflammation

• Published in: Scientific reports Vol. 9; no. 1; pp. 9074 - 14
• Main Authors: Singh, Tania, Colberg, Jesper K., Sarmiento, Luis, Chaves, Patricia, Hansen, Lisbeth, Bsharat, Sara, Cataldo, Luis R., Dudenhöffer-Pfeifer, Monika, Fex, Malin, Bryder, David, Holmberg, Dan, Sitnicka, Ewa, Cilio, Corrado, Prasad, Rashmi B., Artner, Isabella
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.06.2019; Nature Publishing Group
• Subjects: 38; 38/1; 38/39; 38/77; 38/91; 631/208/199; 631/250/38; 64/60; 82; 96; 96/31; Animals; Antigen-Presenting Cells - metabolism; Autoantigens; Autoimmunity; B-Lymphocytes - metabolism; Basic Medicine; Beta cells; Bone marrow; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; Cell activation; Cell and Molecular Biology; Cell- och molekylärbiologi; Gene expression; Gene Expression Regulation; Gene Knockout Techniques; Humanities and Social Sciences; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Inflammation - pathology; Islets of Langerhans - immunology; Islets of Langerhans - pathology; Lymph nodes; Lymphocytes; Lymphocytes T; Maf Transcription Factors, Large - deficiency; Maf Transcription Factors, Large - genetics; Maf Transcription Factors, Large - metabolism; MafB Transcription Factor - deficiency; MafB Transcription Factor - genetics; MafB Transcription Factor - metabolism; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; multidisciplinary; Mutation; Pancreas; Receptors, Antigen, T-Cell - metabolism; Science; Science (multidisciplinary); Signal Transduction; T cell receptors; Thymus; Transcription factors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-45528-x

Maf transcription factors are critical regulators of beta-cell function. We have previously shown that reduced MafA expression in human and mouse islets is associated with a pro-inflammatory gene signature. Here, we investigate if the loss of Maf transcription factors induced autoimmune processes in the pancreas. Transcriptomics analysis showed expression of pro-inflammatory as well as immune cell marker genes. However, clusters of CD4+ T and B220+ B cells were associated primarily with adult MafA −/− MafB +/− , but not MafA −/− islets. MafA expression was detected in the thymus, lymph nodes and bone marrow suggesting a novel role of MafA in regulating immune-cell function. Analysis of pancreatic lymph node cells showed activation of CD4+ T cells, but lack of CD8+ T cell activation which also coincided with an enrichment of naïve CD8+ T cells. Further analysis of T cell marker genes revealed a reduction of T cell receptor signaling gene expression in CD8, but not in CD4+ T cells, which was accompanied with a defect in early T cell receptor signaling in mutant CD8+ T cells. These results suggest that loss of MafA impairs both beta- and T cell function affecting the balance of peripheral immune responses against islet autoantigens, resulting in local inflammation in pancreatic islets.