Transcriptional Changes in Regulatory T Cells From Patients With Autoimmune Polyendocrine Syndrome Type 1 Suggest Functional Impairment of Lipid Metabolism and Gut Homing

Abstract

Autoimmune polyendocrine syndrome type I (APS-1) is a monogenic model disorder of organ-specific autoimmunity caused by mutations in the Autoimmune regulator (AIRE) gene. AIRE facilitates the expression of organ-specific transcripts in the thymus, which is essential for efficient removal of dangerous self-reacting T cells and for inducing regulatory T cells (Tregs). Although reduced numbers and function of Tregs have been reported in APS-I patients, the impact of AIRE deficiency on gene expression in these cells is unknown. Here, we report for the first time on global transcriptional patterns of isolated Tregs from APS-1 patients compared to healthy subjects. Overall, we found few differences between the groups, although deviant expression was observed for the genes TMEM39B, SKIDA1, TLN2, GPR15, FASN, BCAR1, HLA-DQA1, HLA-DQB1, HLA-DRA, GPSM3 and AKR1C3. Of significant interest, the consistent downregulation of GPR15 may indicate failure of Treg gut homing which could be of relevance for the gastrointestinal manifestations commonly seen in APS-1. Upregulated FASN expression in APS-1 Tregs points to increased metabolic activity suggesting a putative link to faulty Treg function. Functional studies are needed to determine the significance of these findings for the immunopathogenesis of APS-1 and for Treg immunobiology in general.

Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma

“…The function of SKIDA1 is relatively understudied. It was found to be differentially expressed in the regulatory T cells of Autoimmune polyendocrine syndrome type I (APS-1) patients compared to healthy patients 102 . SKIDA1 was also described as the best predictor of KMT2A (Mixed-lineage-leukemia) gene rearrangements 103 .…”

Rebooting Regulatory T Cell and Dendritic Cell Function in Immune-Mediated Inflammatory Diseases: Biomarker and Therapy Discovery under a Multi-Omics Lens

“…Recently, the transcriptome of Tregs in the blood of individuals experiencing autoimmune polyendocrine syndrome type I (APS-1) versus healthy controls has been interrogated [ 68 ]. Whereas only subtle changes were observed between disease and healthy groups, the G Protein-Coupled Receptor 15 ( GPR15 ) gene was found significantly downregulated, while the Fatty Acid Synthase ( FASN ) gene was upregulated in APS-1 Tregs [ 68 ].…”

“…Recently, the transcriptome of Tregs in the blood of individuals experiencing autoimmune polyendocrine syndrome type I (APS-1) versus healthy controls has been interrogated [ 68 ]. Whereas only subtle changes were observed between disease and healthy groups, the G Protein-Coupled Receptor 15 ( GPR15 ) gene was found significantly downregulated, while the Fatty Acid Synthase ( FASN ) gene was upregulated in APS-1 Tregs [ 68 ]. Given that individuals with APS-1 suffer from gastrointestinal manifestations and GPR15 is a homing receptor for the gut, it was speculated that GPR15 downregulation might be indicative of a defective influx of Tregs in the gut [ 68 ].…”

“…Whereas only subtle changes were observed between disease and healthy groups, the G Protein-Coupled Receptor 15 ( GPR15 ) gene was found significantly downregulated, while the Fatty Acid Synthase ( FASN ) gene was upregulated in APS-1 Tregs [ 68 ]. Given that individuals with APS-1 suffer from gastrointestinal manifestations and GPR15 is a homing receptor for the gut, it was speculated that GPR15 downregulation might be indicative of a defective influx of Tregs in the gut [ 68 ]. In addition, an increase in FASN, important for fatty acid synthesis, is suggestive of metabolic reprogramming of APS-1 Tregs [ 68 ].…”

“…Given that individuals with APS-1 suffer from gastrointestinal manifestations and GPR15 is a homing receptor for the gut, it was speculated that GPR15 downregulation might be indicative of a defective influx of Tregs in the gut [ 68 ]. In addition, an increase in FASN, important for fatty acid synthesis, is suggestive of metabolic reprogramming of APS-1 Tregs [ 68 ]. However, data were strictly descriptive and deprived of functional evidence, thus results must be considered cautiously.…”