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

Amund Holte Berger,Torgeir Tyssedal,Stefan Johansson,Eystein Sverre Husebye,Anette Susanne Bøe Wolff,Thea Sjøgren,Øyvind Bruserud,Eirik Bratland,Marte Heimli,Bergithe Eikeland Oftedal

doi:10.3389/fimmu.2021.722860

Amund Holte Berger, Torgeir Tyssedal + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2021.722860

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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.

Highlights

Immunological homeostasis and maintenance of health rely on a complex network of structured processes
In order to investigate the impact of Autoimmune regulator (AIRE) mutations on Treg distribution and protein expression within Tregs, PBMCs from five of the nine included APS-1 patients and eight healthy subjects were profiled for common Tregs surface markers using flow cytometry (Figure 1A)
Tregs were identified by the markers CD4+CD25hiFOXP3+, and subtypes hinting at functional properties were assessed within this cohort of cells according to the gating strategy outlined in Figure 1B and shown in Supplementary Figure 1

Summary

Introduction

Immunological homeostasis and maintenance of health rely on a complex network of structured processes. T cells with suppressive capacity, i.e. regulatory T cells (Tregs), constitute about 5-7% of the CD4+ T cell repertoire, and have a critical role in maintaining homeostasis by dampening inexpedient immune responses in the peripheral blood and tissues [1, 2] They are characterized by expression of the linage-defining transcription factor forkhead box P3 (FOXP3), and are equipped with a distinct epigenomic signature, especially at the FOXP3 locus [1,2,3]. They may recirculate back into the adult thymus in order to control thymic output of de novo Tregs [5] Another important aspect of Tregs is their ability to mimic phenotypes of other T cells, e.g. Th1 and Th17 through expression of the relevant signature transcription factors (T-bet and RORgt, respectively) [6, 7], and modulate the environment with their cytokine profile. This has challenged the previous view that the CD4+ cells are static with either a T effector cell or a Treg phenotype

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