Thymic epithelial cell

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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 (blood cell precursors of T cells) 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. [1] [2]

Contents

They are also called epithelial reticular cells, or epithelioreticular cells (ERC). [3]

Groups

The final anatomical location of the thymic gland is reached at 6 weeks in the fetus. TECs originate from non-hematopoietic cells that are characterized by negative expression of CD45 and positive expression of EpCAM. Then TECs are divided into two phenotypically and functionally different groups that have distinct location, cytokeratin expression, surface markers, maturation factors, proteases and function in a T cell selection. Cortical thymic epithelial cells (cTECs) are presented in the outer thymic cortex region, in comparison with medullary thymic epithelial cells (mTECs) located in the inner thymic medulla. Both cTEC and mTEC participate in imposing central and peripheral tolerance. cTECs play a key role in the positive selection and mTECs eliminate auto-reactive thymocytes during the negative selection. [2] Both of these types of cells can be defined and reciprocally distinguished by their expression of cytokines, chemokines, costimulatory molecules, and transcription factors, which have an effect on thymocyte development. [4] TECs, situated in the corticomedullary junction, express two types of cytokeratin: K5 and K8. From these immature progenitors K5+K8+ TECs are derived mTECs with typical expression of K5, K14 and also cTECs, characterized by K8, K18 expression. [2]

Maturation

Medullary thymic epithelial cells' maturation

Maturation of mTEC leads to expression of high levels of MHCII, CD80, autoimmune regulator Aire and tissue restricted antigens (TRAs). Expression of Cathepsin L and Cathepsin S is also typical for mTEC, because of participation of these proteases in the negative selection of T cells. Representative surface markers are UEA-1 and CD80. After maturation continue mTEC to the terminal differentiation stage, which is accompanied by loss of specific maturation factors (MHCII, Aire, CD80, TRA) and initiation of involucrin expression, marker of terminally differentiated epithelium. Remaining MHCIIhi CD80hi, Aire+ mTEC subset will die by apoptosis. [2] [5] [6]

Cortical thymic epithelial cells' maturation

Maturation of cTEC is also mediated by high expression of MHCII molecules but it is combined with proteases β5t, Cathepsin L and TSSP. These factors partake in positive selection of T cells. Specific markers on the surface of cTEC are Ly51 and CD205 and even group of TECs expressing marker CD205 represent one of immature progenitors cells - cTEC committed progenitors. These cells are also called thymic epithelial progenitors cells (TEPCs) and they provide that cortical and medullary epithelial thymocytes share an origin in the postnatal thymus. cTEC-committed progenitor could generate both cTEC and mTEC, in comparison with mTEC-committed progenitor, which is able to produce just mTEC. mTEC-committed progenitors are described by expression of claudin-3 and claudin-4 that are not components of cTEC progeny. [2] [5] [6]

TECs development

The first steps of TEC development are regulated by the transcription factors (Hoxa3, Pax1/9, Eya1, Six1/4, Tbx1), most of which are in postnatal cTEC and immature TECs. The most important transcription factor for all stages of TEC development in embryonic and postnatal thymus is a Foxn1. Foxn1 controls the whole process by the activation of its target genes with binding to specific DNA sequence via its forkhead box domain. There are highlighted over 400 Foxn1 targeted genes, included critical loci for TEC differentiation and function. TEC development require activity of other molecules and transcriptional regulators, such as protein 63 (p63) that is involved in homeostasis of various epithelial lineages, chromobox homolog 4 (Cbx4) which regulates cell proliferation and differentiation, fibroblast growth factors Fgf7 and Fgf10 that initiate TEC expansion, TNFT, CD40, lymfotoxin β receptor (LTβR) and Hedgehog signaling pathway, which could reduce TEC cells in fetal and postnatal thymus. [1] [6] These typical molecules for TEC progenitors development are mostly similar and shared with cTEC. The early stages of cTEC also require high expression of Pax 1/9,Six1/4,Hixa3 but they could be established in the absence of NFκB. In contrast, mTEC development is dependent on the presence of Relb, NFκB signals and the TNFR superfamily but it could be performed in the absence of Foxn1. [1] [6]

Positive and negative selection

Positive selection

Double negative (DN) T cells, as a progenitors with CD44 and CD25 expression but lack of CD4 and CD8 coreceptor expression, are proliferated and differentiated to the double positive (DP) stages. These CD4+ and CD8+ double positive T lymphocytes already express completely recombined TCRs that are tested for recognizing self and non-self molecules by MHCI and MHCII presentation of self antigens on the cTEC. Thymocytes that make adequate interaction with MHC complex, are survived and diverted to either CD4+ or CD8+ single positive (SP) T lymphocytes. These single positive cells migrate out of the cortex to the medulla, where the process continues as a negative selection. [7]

Negative selection

Without negative selection thymocytes are unable to respond to TCR triggering by proliferation, because of a chance of presence auto-reactive T-cell clones. During the negative selection T-lymphocytes acquire competence for elimination of potentially self reactive cells by apoptosis. So if TCR exhibit high or inappropriate affinity for the self antigen expressed on mTEC, the thymocyte will be destroyed. mTEC expressed wide repertoire of self peptides presented on the MHC molecules. Medulla is also important for implementation of self tolerance, which is mediated by CD4+CD25+Foxp3 nTreg cells. Foxp3 Treg development is supported by mTECs during negative selection, when thymocytes have TCR specificities with intermediate affinity for self antigens. [1] [7]

Diseases

TECs, as a component of the thymus, play a key role in thymocyte development and self-tolerance, so their dysfunction causes many autoimmune diseases, tumors of immunodeficiencies. Most frequently are occurred epithelial tumors established from TEC and thymocytes - thymomas and thymic carcinoma. Maturation abnormalities of TECs induce chronic inflammatory diseases and decreased count of mTEC and cTEC leads to chronic inflammatory bowel disease (IBD). Autoimmune disease development is result of a breakdown of the self-tolerance by Aire-mediated TRAs' expression on mTEC or the negative regulatory system formed by CD4+CD25+Foxp3 nTreg cells. Aire mediates negative selection of auto-reactive T-cells and organ-specific antigens' expression on mTECs. The outcome of a single gene mutation in the autoimmune regulator Aire is systematic disease APECED (APS-1), which is manifested by mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. There are many autoimmune diseases, caused by failure of self-tolerance by TRAs on mTEC, for example autoimmune thyroiditis, rheumatoid arthritis or multiple sclerosis. Type 1 diabetes is a result of the absence of self-tolerance, which is characterized by a decreased expression of Insulin 1 and Insulin 2 (TRAs) on mTEC. mTEC and cTEC damage is observed during Graves' disease, Myasthenia gravis or HIV. [2]

See also

List of distinct cell types in the adult human body

Related Research Articles

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<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.

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.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

<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.

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<span class="mw-page-title-main">CD83</span> Human protein

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Thymic nurse cells (TNCs) are large epithelial cells found in the cortex of the thymus and also in cortico-medullary junction. They have their own nucleus and are known to internalize thymocytes through extensions of plasma membrane. The cell surfaces of TNCs and their cytoplasmic vacuoles express MHC Class I and MHC Class II antigens. The interaction of these antigens with the developing thymocytes determines whether the thymocytes undergo positive or negative selection.

Seong Hoe Park is a Korean immunologist and pathologist and a distinguished professor of pathology at the Seoul National University College of Medicine. He served as the chair of the Department of Pathology (2000–2004), the chair of the Graduate Program of Immunology (2002–2006), the president of Center for Animal Resource Development (2004–2006) at Seoul National University. He was the president of the Korean Association of Immunologists (2000–2001). Throughout his career as a T cell immunologist, Park established the theory of T cell-T cell interaction in human thymus, in which T cells expressing MHC class II drive previously unrecognized types of T cells and provide another significant developmental mechanism of T cells.

<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.

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<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.

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.

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.

References

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  2. 1 2 3 4 5 6 Sun, Lina; Li, Hongran; Luo, Haiying; Zhao, Yong (2014). "Thymic Epithelial Cell Development and Its Dysfunction in Human Diseases". BioMed Research International. 2014: 206929. doi: 10.1155/2014/206929 . PMC   3929497 . PMID   24672784.
  3. ↑ S avino W, Santa-Rosa GL (1982). "Histophysiology of thymic epithelial reticular cells". Arch Histol Jpn. 45 (2): 139–44. doi:10.1679/aohc.45.139. PMID   6751281.
  4. ↑ Takahama, Yousuke; Ohigashi, Izumi; Baik, Song; Anderson, Graham (20 March 2017). "Generation of diversity in thymic epithelial cells" (PDF). Nature Reviews Immunology. 17 (5): 295–305. doi:10.1038/nri.2017.12. PMID   28317923. S2CID   13727266.
  5. 1 2 Anderson, Graham; Takahama, Yousuke (June 2012). "Thymic epithelial cells: working class heroes for T cell development and repertoire selection". Trends in Immunology. 33 (6): 256–263. doi:10.1016/j.it.2012.03.005. PMID   22591984.
  6. 1 2 3 4 Sun, Lina; Luo, Haiying; Li, Hongran; Zhao, Yong (15 April 2013). "Thymic epithelial cell development and differentiation: cellular and molecular regulation". Protein & Cell. 4 (5): 342–355. doi:10.1007/s13238-013-3014-0. PMC   4883051 . PMID   23589020.
  7. 1 2 Alexandropoulos, Konstantina; Danzl, Nichole M. (28 March 2012). "Thymic epithelial cells: antigen presenting cells that regulate T cell repertoire and tolerance development". Immunologic Research. 54 (1–3): 177–190. doi:10.1007/s12026-012-8301-y. PMID   22454100. S2CID   207366780.
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