Thymus stromal cells

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Thymus stromal cells are subsets of specialized cells located in different areas of the thymus. [1] 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. [2]

Contents

Structure

The thymus is a primary lymphoid organ of the immune system. It is a butterfly-shaped organ consisting of two lobes, located in the top part of the chest, that supports T cell development via specialized microenvironments that ensure a diverse, functional, and self-tolerant T cell population. These microenvironments are classically defined as distinct cortex and medulla regions that each contain specialized subsets of stromal cells. [3] The stepwise progression of thymocyte development requires their migration through these thymic regions, where interactions with cTEC and mTEC subsets take place. [4]

Function

Thymus stromal cells provide chemokines and cytokines during the early stages of T lymphocyte development, and they are essential for promoting the homing thymic-seeding progenitors, inducing T-lineage differentiation, and supporting thymocyte survival and proliferation. [2] The predominant stromal cells found in the postnatal thymus are thymic epithelial cells (TECs). [5]

cTECs – (cortical thymic epithelial cells) are located in the cortex, and they are responsible for T lineage commitment and positive selection of early thymocytes, [5] [6] cTECs provide cytokines, such as interleukin 7 (IL-7) and SCF complex, to promote early thymocyte progenitor (ETP) proliferation as well as DLL4-mediated Notch signaling to induce the differentiation of ETP toward the T lineage. [2]

mTECs (medullary thymic epithelial cells) in the medulla contribute to the development of T cell tolerance by purging autoreactive T lymphocytes by expression of cell-type-specific genes referred to as tissue-restricted antigens (TRA), [7] and they also participate in the final stages of thymocyte maturation. [5] mTECs also predominantly express receptor RANK, a major mediator of the thymic crosstalk signal, that is involved in the formation of the thymic medulla. [1]

Mesenchymal stromal cells are required to create the thymic microenvironment and to maintain epithelial architecture and function in the thymus during organogenesis. They also serve as the major source of retinoic acid, which promotes the proliferation of cTECs. In the adult thymus, mesenchymal cells are found as fibroblastic cells that express a set of structural proteins and functional molecules, such as collagens, CD34, fibroblast-specific protein-1 (FSP1), platelet-derived growth factor receptor α (PDGFRα). They are crucial for the maintenance and regeneration of mTECs. [1]

Clinical significance

Inborn defects of thymus stromal cells

Inborn errors of thymic stromal cell development and function lead to impaired T cell development resulting in a susceptibility to opportunistic infections and autoimmunity. [8] The most serious clinical expression of a thymic stromal cell defect is profound T cell lymphopaenia, presenting as a complete DiGeorge syndrome or severe combined immune deficiency (T−B+NK+ SCID). [9]

Role in thymus atrophy and aging

There is large evidence indicating the main target of age-linked thymic dysfunction is thymic stroma with a microenvironment consisting of thymic stromal cells. Studies showed that in the thymic stromal cells, especially cTECs, there is (in the case of an aging thymus) deficiency in the peroxide-quenching enzyme catalase. [10] This deficiency renders thymic stromal cells sensitive to damage induced by inflammation and damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS), and then accumulated metabolic damage and oxidative stress promote thymic dysfunction due to age and accelerated thymus atrophy. [11]

Related Research Articles

Thymus 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 specifically to 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.

T cell White blood cells of the immune system

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 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.

Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".

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 thymocytes into mature T cells according to either negative or positive selection. This selection process is vitally important in shaping the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens but remain tolerant towards the body's own antigens. Positive selection selects cells which are able to bind MHC class I or II molecules with at least a weak affinity. This eliminates those T cells which would be non-functional due to an inability to bind MHC. Negative selection destroys thymocytes with a high affinity for self peptides or MHC. This eliminates cells which would direct immune responses towards self-proteins in the periphery. Negative selection is not 100% effective, and some autoreactive T cells escape and are released into the circulation. Additional mechanisms of peripheral tolerance exist to silence these cells, but if these fail, autoimmunity may arise.

Hassalls corpuscles

Hassall's corpuscles are structures found in the medulla of the human thymus, formed from eosinophilic type VI epithelial reticular 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. They are named for Arthur Hill Hassall, who discovered them in 1846.

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 prevents immune response to harmless food antigens and allergens, too. 

CD83

CD83 is a human protein encoded by the CD83 gene.

Thymic stromal lymphopoietin

Thymic stromal lymphopoietin (TSLP) is a protein belonging to the cytokine family. It is known to play an important role in the maturation of T cell populations through activation of antigen-presenting cells.

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.

Lymph node stromal cells are essential to the structure and function of the lymph node whose functions include: creating an internal tissue scaffold for the support of hematopoietic cells; the release of small molecule chemical messengers that facilitate interactions between hematopoietic cells; the facilitation of the migration of hematopoietic cells; the presentation of antigens to immune cells at the initiation of the adaptive immune system; and the homeostasis of lymphocyte numbers. Stromal cells originate from multipotent mesenchymal stem cells.

Immunoediting is a dynamic process that consists of immunosurveillance and tumor progression. It describes the relation between the tumor cells and the immune system. It is made up of three phases: elimination, equilibrium, and escape.

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 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.

Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

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.

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.

Thymoproteasome is a special kind of proteasome, which is present in vertebrates. In the body it is located in thymus, exclusively in cortical thymic epithelial cells (cTECs). But in thymus we can also find another type of specific proteasome, immunoproteasome, which is present in thymocytes, dendritic cells and medular thymic epithelial cells. It was first described in 2007 during a search for non-intronic sequence proximal to PSMB5 locus in mouse genome. The PSMB5 locus encodes the standard β5 proteasome subunit, while this sequence encodes a variant subunit β5t (PSMB11) specific to thymoproteasome. The importance of this protein complex is its involvement in positive selection of T cells.

References

  1. 1 2 3 Nitta, Takeshi; Takayanagi, Hiroshi (2021-01-14). "Non-Epithelial Thymic Stromal Cells: Unsung Heroes in Thymus Organogenesis and T Cell Development". Frontiers in Immunology. 11: 620894. doi: 10.3389/fimmu.2020.620894 . ISSN   1664-3224. PMC   7840694 . PMID   33519827.
  2. 1 2 3 Han, Jianxun; Zúñiga-Pflücker, Juan Carlos (2021-01-15). "A 2020 View of Thymus Stromal Cells in T Cell Development". The Journal of Immunology. 206 (2): 249–256. doi:10.4049/jimmunol.2000889. ISSN   0022-1767. PMC   7909612 . PMID   33397738.
  3. ↑ James, Kieran D.; Jenkinson, William E.; Anderson, Graham (2021-02-25). "Non-Epithelial Stromal Cells in Thymus Development and Function". Frontiers in Immunology. 12: 634367. doi: 10.3389/fimmu.2021.634367 . ISSN   1664-3224. PMC   7946857 . PMID   33717173.
  4. ↑ Gao, Yu; Liu, Ruining; He, Chenfei; Basile, Juan; Vesterlund, Mattias; Wahren-Herlenius, Marie; Espinoza, Alexander; Hokka-Zakrisson, Cassandra; Zadjali, Fahad; Yoshimura, Akihiko; Karlsson, Mikael (2021-03-18). "SOCS3 Expression by Thymic Stromal Cells Is Required for Normal T Cell Development". Frontiers in Immunology. 12: 642173. doi: 10.3389/fimmu.2021.642173 . ISSN   1664-3224. PMC   8012910 . PMID   33815395.
  5. 1 2 3 Bautista, Jhoanne L.; Cramer, Nathan T.; Miller, Corey N.; Chavez, Jessica; Berrios, David I.; Byrnes, Lauren E.; Germino, Joe; Ntranos, Vasilis; Sneddon, Julie B.; Burt, Trevor D.; Gardner, James M. (December 2021). "Single-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla". Nature Communications. 12 (1): 1096. Bibcode:2021NatCo..12.1096B. doi:10.1038/s41467-021-21346-6. ISSN   2041-1723. PMC   7889611 . PMID   33597545.
  6. ↑ Wang, Hong-Xia; Pan, Wenrong; Zheng, Lei; Zhong, Xiao-Ping; Tan, Liang; Liang, Zhanfeng; He, Jing; Feng, Pingfeng; Zhao, Yong; Qiu, Yu-Rong (2020-01-31). "Thymic Epithelial Cells Contribute to Thymopoiesis and T Cell Development". Frontiers in Immunology. 10: 3099. doi: 10.3389/fimmu.2019.03099 . ISSN   1664-3224. PMC   7005006 . PMID   32082299.
  7. ↑ Miragaia, Ricardo J.; Zhang, Xiuwei; Gomes, Tomás; Svensson, Valentine; Ilicic, Tomislav; Henriksson, Johan; Kar, Gozde; Lönnberg, Tapio (December 2018). "Single-cell RNA-sequencing resolves self-antigen expression during mTEC development". Scientific Reports. 8 (1): 685. Bibcode:2018NatSR...8..685M. doi:10.1038/s41598-017-19100-4. ISSN   2045-2322. PMC   5766627 . PMID   29330484.
  8. ↑ Kreins, Alexandra Y.; Bonfanti, Paola; Davies, E. Graham (2021-03-18). "Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects". Frontiers in Immunology. 12: 655354. doi: 10.3389/fimmu.2021.655354 . ISSN   1664-3224. PMC   8012524 . PMID   33815417.
  9. ↑ Kreins, Alexandra Y.; Maio, Stefano; Dhalla, Fatima (February 2021). "Inborn errors of thymic stromal cell development and function". Seminars in Immunopathology. 43 (1): 85–100. doi:10.1007/s00281-020-00826-9. ISSN   1863-2297. PMC   7925491 . PMID   33257998.
  10. ↑ Du, Hongmei; Wang, Yajun; Liu, Xue; Wang, Siliang; Wu, Simeng; Yuan, Zhe; Zhu, Xike (January 2021). "miRNA-146a-5p mitigates stress-induced premature senescence of D-galactose-induced primary thymic stromal cells". Cytokine. 137: 155314. doi:10.1016/j.cyto.2020.155314. PMID   33002743. S2CID   222161158.
  11. ↑ Cepeda, Sergio; Griffith, Ann V. (May 2018). "Thymic stromal cells: Roles in atrophy and age-associated dysfunction of the thymus". Experimental Gerontology. 105: 113–117. doi:10.1016/j.exger.2017.12.022. PMC   5869099 . PMID   29278750.
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