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

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.publishedVersio

Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection

To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors (TCRs) are negatively selected, however, divergence into tolerogenic, agonist selected lineages represent an alternative fate. As thymocyte development, selection, and lineage choices are dependent on spatial context and cell-to-cell interactions, we have performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and spatial transcriptomics on paediatric human thymu​​s. Thymocytes expressing markers of strong TCR signalling diverged from the conventional developmental trajectory prior to CD4+ or CD8+ lineage commitment, while markers of different agonist selected T cell populations (CD8αα(I), CD8αα(II), T(agonist), Treg(diff), and Treg) exhibited variable timing of induction. Expression profiles of chemokines and co-stimulatory molecules, together with spatial localisation, supported that dendritic cells, B cells, and stromal cells contribute to agonist selection, with different subsets influencing thymocytes at specific developmental stages within distinct spatial niches. Understanding factors influencing agonist T cells is needed to benefit from their immunoregulatory effects in clinical use

Characterization of regulatory T cells in Autoimmune Polyendocrine Syndrome type I, a model disease for autoimmunity

The T and B lymphocytes of the adaptive immune system face the challenge of correctly recognizing antigens originating from a vast number of rapidly evolving pathogens, while ignoring those pertaining to the host itself. A failure to ensure such self-tolerance may lead to autoimmune responses, the cause of a wide range of adverse pathologies. One self-tolerance mechanism is the negative selection of developing T cell progenitors with self-reactive capabilities in the thymus, another is the peripheral tolerance inferred by regulatory T cells (T_regs). The Autoimmune Regulator (AIRE), which induces the ectopic expression of tissuerestricted antigens in the thymus, has been indicated to be of importance in both central and peripheral tolerance. Mutations in the AIRE gene is the cause of autoimmune polyendocrine syndrome type I (APS-1), an established model disease for autoimmunity. In this project, we aimed to characterize expression patterns in T_regs in APS-1, both at the protein and RNA levels. By assessment of the expression of pre-selected candidate genes, a number of subtle trends could be observed. It was indicated that the thymic output of T_regs was lower in APS-1 patients compared to healthy controls, but that the patient’s T_regs were capable of inducing expression of genes associated with an activated state. However, the observations failed to reach statistical significance, preventing reliable conclusions. The exception is a significant increase in the expression of mTOR, a downstream mediator of signaling though PKB/Akt. This is of interest as the inhibition of PKB/Akt by the PTEN phosphatase appear to be important for T_reg lineage identity. When using RNA sequencing to perform a global search for gene expression perturbations, a number of genes were found to exhibit significant changes in expression levels in T_regs from APS-1 patients compared to the controls. Among the genes indicated to be significantly perturbed are SKI and NOTCH-1, potentially affecting TGF-b signaling. TGF-b has been suggested to have implications in T_reg suppressive function and in the induction of the regulatory T cell phenotype. Further validation of these results, and elucidation of their functional implications, would be relevant for future work. Our hope is that continued work on T_reg biology, and identification of clinically relevant biomarkers, can contribute to the successful implementation of this cell population in diagnostics and treatment of patients with immune-mediated diseases

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

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