Thymic epithelial cells (TECs) are specialized

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...

s with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The

thymus 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. ...

, as a

primary lymphoid organ The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...

, mediates

T cell A T cell is a type of lymphocyte. T cells are one of the important 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 r ...

development and maturation. The thymic microenvironment is established by TEC network filled with

thymocytes 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. Thymopoiesis describes the process which turns thymo ...

(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 Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by ...

. Dysfunction of TECs causes several

immunodeficiencies Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...

and

autoimmune diseases An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

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

Groups

The final anatomical location of the thymic gland is reached at 6 weeks in the

fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...

. 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 Cortical thymic epithelial cells (cTECs) form unique parenchyma cell population of the thymus which critically contribute to the development of T cells. Thymus tissue is compartmentalized into cortex and medulla and each of these two compartmen ...

(cTECs) are presented in the outer thymic cortex region, in comparison with

medullary thymic epithelial cells 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 functiona ...

(mTECs) located in the inner thymic medulla. Both cTEC and mTEC participate in imposing central and

peripheral tolerance In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery (after T and B cells egress from primary lymphoid organs). Its main purpose is to ensure that ...

. cTECs play a key role in the

positive selection In population genetics, directional selection, is a mode of negative natural selection in which an extreme phenotype is favored over other phenotypes, causing the allele frequency to shift over time in the direction of that phenotype. Under dir ...

and mTECs eliminate auto-reactive thymocytes during the negative selection. Both of these types of cells can be defined and reciprocally distinguished by their expression of

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...

, costimulatory molecules, and

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...

, which have an effect on thymocyte development. TECs, situated in the corticomedullary junction, express two types of

cytokeratin Cytokeratins are keratin proteins found in the intracytoplasmic cytoskeleton of epithelial tissue. They are an important component of intermediate filaments, which help cells resist mechanical stress. Expression of these cytokeratins within epit ...

: 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.

Maturation

Medullary thymic epithelial cells' maturation

Maturation of mTEC leads to expression of high levels of

MHCII MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial ce ...

, CD80, autoimmune regulator

Aire Aire may refer to: Music * ''Aire'' (Yuri album), 1987 * ''Aire'' (Pablo Ruiz album), 1997 *''Aire (Versión Día)'', an album by Jesse & Joy Places *Aire-sur-la-Lys, a town in the Pas-de-Calais département in France *Aire-la-Ville, a municip ...

and tissue restricted antigens (TRAs). Expression of Cathepsin L and

Cathepsin S Cathepsin S is a protein that in humans is encoded by the ''CTSS'' gene. Transcript variants utilizing alternative polyadenylation signals exist for this gene. Cathepsin S is a member of the peptidase C1 family of cysteine cathepsins, a lysosomal ...

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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

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 CD 205 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 Clandin 3 and Clandin 4 that are not components of cTEC progeny.

TECs development

The first steps of TEC development are regulated by the

(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 Forkhead box protein N1 is a protein that in humans is encoded by the ''FOXN1'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ...

. Foxn1 controls the whole process by the activation of its target genes with binding to specific DNA sequence via its

forkhead box FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryon ...

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 Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...

Fgf7 and Fgf10 that initiate TEC expansion, TNFT, CD40, lymfotoxin β receptor (LTβR) and

Hedgehog signaling pathway The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathwa ...

, which could reduce TEC cells in fetal and postnatal thymus. 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 The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growth ...

superfamily but it could be performed in the absence of Foxn1.

Positive and negative selection

Positive selection

Double negative (DN) T cells, as a progenitors with CD44 and CD25 expression but lack of

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...

and

CD8 CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen in ...

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

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.{{cite journal , last1=Alexandropoulos , first1=Konstantina , last2=Danzl , first2=Nichole M. , title=Thymic epithelial cells: antigen presenting cells that regulate T cell repertoire and tolerance development , journal=Immunologic Research , date=28 March 2012 , volume=54 , issue=1–3 , pages=177–190 , doi=10.1007/s12026-012-8301-y, pmid=22454100 , s2cid=207366780

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.

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 A thymoma is a tumor originating from the epithelial cells of the thymus that is considered a rare malignancy. Thymomas are frequently associated with neuromuscular disorders such as myasthenia gravis; thymoma is found in 20% of patients with mya ...

and

thymic carcinoma Thymic carcinoma, or type C thymoma, is a malignancy of the thymus. It is a rare cancer that is often diagnosed at advanced stages. Recurrence following treatment is common, and thymic carcinoma is associated with a poor prognosis. Epidemiology ...

. 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 break down 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 Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid's cells, thereby destroying it. It may ...

, 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 Graves' disease (german: Morbus Basedow), also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyr ...

Myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, dro ...

or HIV.

References

Thymus Epithelial cells