Thymic mimetic cells

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Thymic mimetic cells are a heterogeneous population of cells located in the thymus that exhibit phenotypes of a wide variety of differentiated peripheral cells. They arise from medullary thymic epithelial cells (mTECs) and also function in negative selection of self-reactive T cells. [1]

Contents

History

Some subsets of these cells were observed as early as the mid-1800s because of their distinct, seemingly misplaced, phenotype. The most readily observed subsets were those accumulating and forming microscopic structures, most notably Hassall's corpuscles resembling skin keratinocytes. Many subsets with a more dispersed distribution were found later. Substantial progress has been made in recent years owing to the rapid development of single cell sequencing methods, such as scRNA-seq or scATAC-seq. [1]

Diversity

Although thymic mimetic cells exhibit transcriptional programmes of cells from other tissues, they are not identical to them and share a part of their gene expression with mTECs from which they arise. The entire range of phenotypes as well as the pathways that lead to them are still in need of further research. A recent review recognizes (based on expression of lineage specific transcription factors and cell products) the following subtypes: Basal (skin/lung) mTEC, Enterocyte/hepatocyte mTEC, Ciliated mTEC, Ionocyte mTEC, Keratinocyte mTEC, Microfold mTEC, Muscle mTEC, Neuroendocrine mTEC, Parathyroid mTEC, Secretory mTEC, Thyroid mTEC, Tuft mTEC. [1] [2]

Function

Since its discovery in 2001, [3] AIRE (Autoimmune regulator) has been the main focus of studies of thymic (central) immune tolerance. AIRE induces the expression of many antigens specific to differentiated cells not found in the thymus (termed peripheral tissue antigens or tissue restricted antigens) thus helping to detect and remove T cells that react with these antigens. [4] The mechanism of AIRE is complicated and there are reasons to believe that it is not the sole mechanism of TRA (tissue restricted antigen) expression. AIRE is not sequence specific making its action stochastic and not well targeted, TRAs can also be detected in cells with AIRE knocked out [5] and patients with AIRE deficiency (APS-1) share some autoimmune symptoms but can have other symptoms which are not shared by most. [6]

The expression of peripheral antigens in mimetic cells strongly implies a function in establishing central immune tolerance. This has been reported [7] but further studies are needed. It is unknown what prompts the mTECs to differentiate into mimetic cells, the lineage specific transcription factors could be induced by AIRE or perhaps other signals. Lineage specific transcription factors expressed by some mimetic cell subtypes have been associated with autoimmune disorders. [1] [8] [9] [10] [11]

In addition, some mimetic cells can shape the environment and function of the thymus by producing cytokines. [12] [13]

Related Research Articles

<span class="mw-page-title-main">Thymus</span> Endocrine gland

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation.

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

<span class="mw-page-title-main">Hassall's corpuscles</span>

Hassall's corpuscles are structures found in the medulla of the human thymus, formed from eosinophilic type VI thymic epithelial cells arranged concentrically. These concentric corpuscles are composed of a central mass, consisting of one or more granular cells, and of a capsule formed of epithelioid cells. They vary in size with diameters from 20 to more than 100μm, and tend to grow larger with age. They can be spherical or ovoid and their epithelial cells contain keratohyalin and bundles of cytoplasmic fibres. Later studies indicate that Hassall's corpuscles differentiate from medullary thymic epithelial cells after they lose autoimmune regulator (AIRE) expression. This makes them an example of Thymic mimetic cells. They are named for Arthur Hill Hassall, who discovered them in 1846.

<span class="mw-page-title-main">Autoimmune regulator</span> Immune system protein

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. It is a 13kbp gene on chromosome 21q22.3 that encodes 545 amino acids. AIRE is a transcription factor expressed in the medulla of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

Self-protein refers to all proteins endogenously produced by DNA-level transcription and translation within an organism of interest. This does not include proteins synthesized due to viral infection, but may include those synthesized by commensal bacteria within the intestines. Proteins that are not created within the body of the organism of interest, but nevertheless enter through the bloodstream, a breach in the skin, or a mucous membrane, may be designated as “non-self” and subsequently targeted and attacked by the immune system. Tolerance to self-protein is crucial for overall wellbeing; when the body erroneously identifies self-proteins as “non-self”, the subsequent immune response against endogenous proteins may lead to the development of an autoimmune disease.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance can also serve a purpose in preventing an immune response to harmless food antigens and allergens.

<span class="mw-page-title-main">IKZF1</span> Protein-coding gene in the species Homo sapiens

DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1 gene.

In immunology, clonal deletion is the process of removing T and B lymphocytes from the immune system repertoire. The process of clonal deletion helps prevent recognition and destruction of the self host cells, making it a type of negative selection. Ultimately, clonal deletion plays a role in central tolerance. Clonal deletion can help protect individuals against autoimmunity, which is when an organism produces and immune response on its own cells. It is one of many methods used by the body in immune tolerance.

Alfred Singer is an American immunologist who works at the National Institutes of Health (NIH), where he is the Chief of the Experimental Immunology Branch of the National Cancer Institute (NCI) Center for Cancer Research. He is best known for his work regarding lymphocyte development, particularly the differentiation of immature CD4+8+ thymocytes into mature T cells. Singer's work is foundational in the understanding of T cells and MHC-restricted antigen recognition.

<span class="mw-page-title-main">Medullary thymic epithelial cells</span>

Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

Antigen transfer in the thymus is the transmission of self-antigens between thymic antigen-presenting cells which contributes to the establishment of T cell central tolerance.

<span class="mw-page-title-main">Cortical thymic epithelial cells</span>

Cortical thymic epithelial cells (cTECs) form unique parenchyma cell population of the thymus which critically contribute to the development of T cells.

Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The thymus, as a primary lymphoid organ, mediates T cell development and maturation. The thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production of functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.

Promiscuous gene expression (PGE), formerly referred to as ectopic expression, is a process specific to the thymus that plays a pivotal role in the establishment of central tolerance. This phenomenon enables generation of self-antigens, so called tissue-restricted antigens (TRAs), which are in the body expressed only by one or few specific tissues. These antigens are represented for example by insulin from the pancreas or defensins from the gastrointestinal tract. Antigen-presenting cells (APCs) of the thymus, namely medullary thymic epithelial cells (mTECs), dendritic cells (DCs) and B cells are capable to present peptides derived from TRAs to developing T cells and hereby test, whether their T cell receptors (TCRs) engage self entities and therefore their occurrence in the body can potentially lead to the development of autoimmune disease. In that case, thymic APCs either induce apoptosis in these autoreactive T cells or they deviate them to become T regulatory cells, which suppress self-reactive T cells in the body that escaped negative selection in the thymus. Thus, PGE is crucial for tissues protection against autoimmunity.

Thymus stromal cells are subsets of specialized cells located in different areas of the thymus. They include all non-T-lineage cells, such as thymic epithelial cells (TECs), endothelial cells, mesenchymal cells, dendritic cells, and B lymphocytes, and provide signals essential for thymocyte development and the homeostasis of the thymic stroma.

References

  1. 1 2 3 4 Michelson, Daniel A.; Mathis, Diane (October 2022). "Thymic mimetic cells: tolerogenic masqueraders". Trends in Immunology. 43 (10): 782–791. doi:10.1016/j.it.2022.07.010. ISSN   1471-4906. PMC   9509455 . PMID   36008259.
  2. ↑ Sin, Jun Hyung; Sucharov, Juliana; Kashyap, Sujit; Wang, Yi; Proekt, Irina; Liu, Xian; Parent, Audrey V.; Gupta, Alexander; Kastner, Philippe; Chan, Susan; Gardner, James M.; Ntranos, Vasilis; Miller, Corey N.; Anderson, Mark S.; Schjerven, Hilde (2023-10-27). "Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance". Science Immunology. 8 (88): eabq3109. doi:10.1126/sciimmunol.abq3109. ISSN   2470-9468. PMID   37889983.
  3. ↑ Derbinski, Jens; Schulte, Antje; Kyewski, Bruno; Klein, Ludger (November 2001). "Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self". Nature Immunology. 2 (11): 1032–1039. doi:10.1038/ni723. ISSN   1529-2916. PMID   11600886. S2CID   20155713.
  4. ↑ Perniola, Roberto (2018). "Twenty Years of AIRE". Frontiers in Immunology. 9: 98. doi: 10.3389/fimmu.2018.00098 . ISSN   1664-3224. PMC   5816566 . PMID   29483906.
  5. ↑ Sansom, Stephen N.; Shikama-Dorn, Noriko; Zhanybekova, Saule; Nusspaumer, Gretel; Macaulay, Iain C.; Deadman, Mary E.; Heger, Andreas; Ponting, Chris P.; Holländer, Georg A. (December 2014). "Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia". Genome Research. 24 (12): 1918–1931. doi:10.1101/gr.171645.113. ISSN   1088-9051. PMC   4248310 . PMID   25224068.
  6. ↑ Meloni, Antonella; Willcox, Nick; Meager, Anthony; Atzeni, Michela; Wolff, Anette S. B.; Husebye, Eystein S.; Furcas, Maria; Rosatelli, Maria Cristina; Cao, Antonio; Congia, Mauro (April 2012). "Autoimmune Polyendocrine Syndrome Type 1: An Extensive Longitudinal Study in Sardinian Patients". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1114–1124. doi: 10.1210/jc.2011-2461 . ISSN   0021-972X. PMID   22344197.
  7. ↑ Michelson, Daniel A.; Hase, Koji; Kaisho, Tsuneyasu; Benoist, Christophe; Mathis, Diane (July 2022). "Thymic epithelial cells co-opt lineage-defining transcription factores to eliminate autoreactive T cells". Cell. 185 (14): 2542–2558.e18. doi:10.1016/j.cell.2022.05.018. ISSN   0092-8674. PMC   9469465 . PMID   35714609.
  8. ↑ The UK IBD Genetics Consortium; The Wellcome Trust Case Control Consortium 2 (December 2009). "Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region". Nature Genetics. 41 (12): 1330–1334. doi:10.1038/ng.483. ISSN   1061-4036. PMC   2812019 . PMID   19915572.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  9. ↑ Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C. A.; Patsopoulos, Nikolaos A.; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E.; Edkins, Sarah; Gray, Emma; Booth, David R.; Potter, Simon C.; Goris, An (August 2011). "Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis". Nature. 476 (7359): 214–219. Bibcode:2011Natur.476..214T. doi:10.1038/nature10251. ISSN   1476-4687. PMC   3182531 . PMID   21833088.
  10. ↑ Liu, Xiangdong; Invernizzi, Pietro; Lu, Yue; Kosoy, Roman; Lu, Yan; Bianchi, Ilaria; Podda, Mauro; Xu, Chun; Xie, Gang; Macciardi, Fabio; Selmi, Carlo; Lupoli, Sara; Shigeta, Russell; Ransom, Michael; Lleo, Ana (August 2010). "Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis". Nature Genetics. 42 (8): 658–660. doi:10.1038/ng.627. ISSN   1546-1718. PMC   3150510 . PMID   20639880.
  11. ↑ Sin, Jun Hyung; Sucharov, Juliana; Kashyap, Sujit; Wang, Yi; Proekt, Irina; Liu, Xian; Parent, Audrey V.; Gupta, Alexander; Kastner, Philippe; Chan, Susan; Gardner, James M.; Ntranos, Vasilis; Miller, Corey N.; Anderson, Mark S.; Schjerven, Hilde (2023-10-27). "Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance". Science Immunology. 8 (88): eabq3109. doi:10.1126/sciimmunol.abq3109. ISSN   2470-9468. PMID   37889983.
  12. ↑ Miller, Corey N.; Proekt, Irina; von Moltke, Jakob; Wells, Kristen L.; Rajpurkar, Aparna R.; Wang, Haiguang; Rattay, Kristin; Khan, Imran S.; Metzger, Todd C.; Pollack, Joshua L.; Fries, Adam C.; Lwin, Wint W.; Wigton, Eric J.; Parent, Audrey V.; Kyewski, Bruno (July 2018). "Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development". Nature. 559 (7715): 627–631. Bibcode:2018Natur.559..627M. doi:10.1038/s41586-018-0345-2. ISSN   1476-4687. PMC   6062473 . PMID   30022164.
  13. ↑ Watanabe, Norihiko; Wang, Yi-Hong; Lee, Heung Kyu; Ito, Tomoki; Wang, Yui-Hsi; Cao, Wei; Liu, Yong-Jun (August 2005). "Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus". Nature. 436 (7054): 1181–1185. doi:10.1038/nature03886. ISSN   1476-4687. PMID   16121185. S2CID   4387582.
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