Functional studies of thymus and T cells with relation to autoimmunity
Type 1 diabetes (T1D) arise due to an immunological T cell attack towards own tissue and cells. The T cells are normally educated in thymus to avoid autoimmunity. Genetic T1D risk variants are mainly regulatory, and we have previously found that several influence immune gene expression in thymus and through bulk RNA seq identified which cell types express the T1D risk genes. Currently, we have shifted focus to a single cell perspective to further understand the cellular and molecular mechanisms of self-tolerance. We are generating a comprehensive overview of human thymic cell populations existing using single cell and spatial transcriptomics. We also investigate the T cell receptors in thymic T cells at different developmental stages. Underlying regulatory mechanisms for thymic presentation of all peripheral proteins are explored by ChIP sequencing of binding sites for the transcription factors AIRE, DEAF1 and FEZF2. Our goal is to better understand the autoimmune process of T1D.
Primary Investigator: Benedicte A. Lie
News 2022:
In addition to working on specific diseases, we aim to understand central mechanisms of autoimmunity particularly related to establishment of self-tolerant T cells in thymus. Tolerogenic and regulatory T cells represent a putative path to inhibit self-reactive T cells in order to prevent autoimmunity, including type 1 diabetes. To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors 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 single cell sequencing and spatial transcriptomics of paediatric human thymus. 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 enable future clinical use of their immunoregulatory effects.
Additionally, we have been involved in a study on the immune receptors KIR (killer cell immunoglobulin-like receptor) and in particular determination of KIR3DL1/S1 genotypes for medical application, which is hampered by complex sequence and structural variation. We therefore developed a model for imputing these genotypes from surrounding polymorphisms, and we plan to apply this method in future investigations of the role of KIR variants in autoimmune diseases.
Publications 2022:
We have several publications on different autoimmune diseases. The publications relevant to type 1 diabetes this year are:
Heimli M, Flåm ST, Hjorthaug HS, Trinh D, Frisk M, Dumont KA, Ribarska T, Tekpli X, Saare M, Lie BA. Multimodul human thymic profiling reveals trajectories and cellular milieu for T against selection. Front Immunol 2023, 13, 1092028. doi: 10.3389/fimmu.2022.1092028