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Rattay lab

The research in the Rattay Laboratory focuses on deciphering the cellular and molecular mechanisms underlying central immune tolerance and the development of autoimmunity. A particular interest lies in the development and tissue homeostasis of the thymus, the organ in which T-cell development and selection occur.

The cell-cell communication between lymphocytes and thymic epithelial cells plays a pivotal role in lymphocyte migration and the establishment of central immune tolerance. The cellular crosstalk between thymic epithelial cells, endothelial cells and lymphocytes is studied using whole genome sequencing expression analysis, fluorescence high-resolution microscopy and 3D culture systems among other methods.

Thymic epithelial cells and dendritic cells present self-peptides on MHC to developing thymocytes and mediate thymic selection. The molecular mechanisms regulating self-peptide expression in thymic epithelial cells are studied using single cell and bulk RNA-sequencing, ATAC-sequencing, ChIP-sequencing and bioinformatic approaches.

A better understanding of thymic tissue homeostasis and cell-cell communication in health and disease will ultimately help to develop better treatments for autoimmune diseases, inflammatory diseases and thymic epithelial cancers such as thymoma and thymic carcinoma.

 ――― We are currently hiring PhDs and Postdocs! ―――

If you are interested in joining our team kindly send your letter of motivation and your CV (incl. publications and reference contacts) as a single PDF to Prof. Dr. Kristin Rattay;

#central tolerance #immunopharmacology #thymus #autoimmunity #omics in immunology #systems immunology #signaling #cell-cell communication

The projects in the laboratory cover the following main research topics:

Thymic tissue development, homeostasis and cell-cell communication

Lymphocyte pools are under steady turnover and get constantly replenished by newly developed cells. The progenitors of T-lymphocytes originate from hematopoietic progenitor cells in the bone marrow and traffic to the thymus where they differentiate and undergo maturation and selection (i.e., positive and negative selection). Proper thymus function essentially depends on cell-cell interactions between different cell types:

I.       Between T-lymphocyte progenitors and endothelial cells during immigration from the blood into the stroma

II.      Between developing T-lymphocytes and epithelial cells (medullary and cortical, mTECs and cTECs, respectively) and dendritic cells (DCs) for positive and negative selection

III.     Between T-cells and endothelial cells for egress into the blood

The research group aims at elucidating the cellular and molecular mechanisms underlying thymic tissue homeostasis during development and to better understand the crosstalk between the different cell types shaping the efficiency of central tolerance.

Thymic self-peptide repertoire transcription, translation and presentation

Immunological tolerance is essential in order to avoid immune reactions towards self-peptides; namely autoimmune reactions. Central tolerance induction occurs in the thymus mediated by different sets of thymic antigen-presenting cells (APCs) including thymic epithelial cells (i.e., cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs)), dendritic cells (DCs) and thymic B cells.

These thymic APCs present endogenously transcribed and imported peripheral peptides on major histocompatibility complex (MHC) class I and II molecules on their surfaces to developing T cells. When clonotypic TCRs bind to self-antigen/MHC complexes above a certain threshold, the respective auto-reactive T cells will be either purged from the repertoire by deletion or fate-diverted into regulatory T cells. Among these thymic APCs, mTECs stand out due to their ability to promiscuously express the majority of tissue-restricted self-antigens (TRAs) and thus by themselves largely procure self-tolerance against peripheral tissues.

The lab studies the development of mTECs and their different subsets with regards to their role in central immune tolerance induction. The regulatory mechanisms involved in gene expression in mTECs are analyzed in order to better understand the highly complex transcriptional profiles in mTECs and the heterogeneity of the mTEC population.

Selected Publications

Miller, C.N., Proekt, I., von Moltke, J., Wells, K.L., Rajpurkar, A.R., Wang, H., Rattay, K., Khan, I.S., Metzger, T.C., Pollack, J.L., et al. (2018). Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature 559, 627-631.

Rattay, K., Meyer, H.V., Herrmann, C., Brors, B., and Kyewski, B. (2016). Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells. J Autoimmun 67, 65-75.

Brennecke, P., Reyes, A., Pinto, S., Rattay, K., Nguyen, M., Kuchler, R., Huber, W., Kyewski, B., and Steinmetz, L.M. (2015). Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat Immunol 16, 933-941.

O. Ucar and K. Rattay (2015). Promiscuous gene expression in the thymus: a matter of epigenetics, miRNA and more? Front. Immunol., vol. 6, p. 93.

Rattay, K., Claude, J., Rezavandy, E., Matt, S., Hofmann, T.G., Kyewski, B., and Derbinski, J. (2015). Homeodomain-interacting protein kinase 2, a novel autoimmune regulator interaction partner, modulates promiscuous gene expression in medullary thymic epithelial cells. J Immunol 194, 921-928.

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