Thymocyte

Last updated

Thymocytes are hematopoietic progenitor cells present in the thymus. [1] Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes. The primary function of thymocytes is the generation of T lymphocytes (T cells). The thymus provides an inductive environment, which allows for the development and selection of physiologically useful T cells. The processes of beta-selection, positive selection, and negative selection shape the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens and are immunologically tolerant towards self antigens.

Contents

Stages of maturation

Thymocytes are classified into a number of distinct maturational stages based on the expression of cell surface markers. The earliest thymocyte stage is the double negative stage (negative for both CD4 and CD8), which more recently has been better described as Lineage-negative, and which can be divided into four substages. The next major stage is the double positive stage (positive for both CD4 and CD8). The final stage in maturation is the single positive stage (positive for either CD4 or CD8).

In mice

StageDefining surface markersLocationSignificant events
Double negative 1 or ETP (Early T lineage Progenitor)Lineage-CD44+CD25-CD117+cortexProliferation, Loss of B and myeloid potentials
Double negative 2Lineage-CD44+CD25+CD117+cortex-
Double negative 3Lineage-CD44-CD25+cortexTCR-beta rearrangement, beta selection
Double negative 4Lineage-CD44-CD25-cortex-
Double positive CD4+CD8+cortexTCR-alpha rearrangement, positive selection, negative selection
Single positiveCD4+CD8- or CD4-CD8+medullaNegative selection

In humans

In human, circulating CD34+ hematopoietic stem cells (HSC) reside in bone marrow. They produce precursors of T lymphocytes, which seed the thymus (thus becoming thymocytes) and differentiate under influence of the Notch and its ligands.

Early, double negative thymocytes express (and can be identified by) CD2, CD5 and CD7. Still during the double negative stage, CD34 expression stops and CD1 is expressed. Expression of both CD4 and CD8 makes them double positive, and matures into either CD4+ or CD8+ cells. [2]

Events during maturation

type:functional (beta selection)functional (positive selection)autoreactive (negative selection)
location:cortexcortexcortex/medulla
Intrathymic T Cell Differentiation.JPG

In order to pass the β-selection checkpoint, the β chain of the T cell receptor rearranged by the thymocyte must retain the structural properties allowing it to be presented on the surface of the thymocyte with pre-TCRα. This eliminates thymocytes with gross defects introduced into the T cell receptor by gene rearrangement.

In order to be positively-selected, thymocytes will have to interact with several cell surface molecules, MHC, to ensure reactivity and specificity. [3]

Positive selection selects cells with a T cell receptor able to bind MHC class I or II molecules with at least a weak affinity. This eliminates (by a process called "death by neglect") those T cells which would be non-functional due to an inability to bind MHC.

Negative selection is the active induction of apoptosis in 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, some autoreactive T cells escape thymic censorship, and are released into the circulation.

Additional mechanisms of tolerance active in the periphery exist to silence these cells such as anergy, deletion, and regulatory T cells. If these peripheral tolerance mechanisms also fail, autoimmunity may arise.

Thymus settling

Thymocytes are ultimately derived from bone marrow hematopoietic progenitor cells [see hematopoietic stem cell, hematopoiesis] which reach the thymus through the circulation. [4] The number of progenitors that enter the thymus each day is thought to be extremely small. Therefore, which progenitors colonize the thymus is unknown. Currently Early Lymphoid Progenitors (ELP) are proposed to settle the thymus and are likely the precursors of at least some thymocytes. ELPs are Lineage-CD44+CD25-CD117+ and thus closely resemble ETPs, the earliest progenitors in the thymus. Precursors enter the thymus at the cortico-medullary junction. Molecules known to be important for thymus entry include P-selectin (CD62P), and the chemokine receptors CCR7 and CCR9. [5]

Following thymus entry, progenitors proliferate to generate the ETP population. This step is followed by the generation of DN2 thymocytes which migrate from the cortico-medullary junction toward the thymus capsule. DN3 thymocytes are generated at the subcapsular zone.

In addition to proliferation, differentiation and T lineage commitment occurs within the DN thymocyte population. Commitment, or loss of alternative lineage potentials (such as myeloid, B, and NK lineage potentials), is dependent on Notch signaling, and is complete by the DN3 stage. Following T lineage commitment, DN3 thymocytes undergo β-selection. [6]

β-selection

Histology of the thymus showing the cortex and medulla Thymus.JPG
Histology of the thymus showing the cortex and medulla
Minute structure of thymus. Gray1179.png
Minute structure of thymus.

The ability of T cells to recognize foreign antigens is mediated by the T cell receptor (TCR), which is a surface protein able to recognize short protein sequences (peptides) that are presented on MHC. The purpose of thymocyte development is to produce mature T cells with a diverse array of functional T cell receptors, through the process of TCR gene rearrangement.

Unlike most genes, which have a stable sequence in each cell which expresses them, the T cell receptor is made up of a series of alternative gene fragments. In order to create a functional T cell receptor, the double negative thymocytes use a series of DNA-interacting enzymes to clip the DNA and bring separate gene fragments together. The outcome of this process is that each T cell receptor has a different sequence, due to different choice of gene fragments and the errors introduced during the cutting and joining process (see section on V(D)J recombination for more information on TCR rearrangement). The evolutionary advantage in having a large number of unique T cell receptors is that each T cell is capable of recognizing a different peptide, providing a defense against rapidly evolving pathogens. [7]

TCR rearrangement occurs in two steps. First the TCRβ chain is rearranged at the DN3 stage of T cell development. The TCRβ chain is paired with the pre-Tα to generate the pre-TCR. The cellular disadvantage in the rearrangement process is that many of the combinations of the T cell receptor gene fragments are non-functional. To eliminate thymocytes which have made a non-functional T cell receptor, only cells that have successfully rearranged the beta chain to produce a functional pre-TCR are allowed to develop beyond the DN3 stage. Cells that fail to produce a functional pre-TCR are eliminated by apoptosis. This process is referred to as the beta-selection checkpoint. Successful beta-selection requires that TCRβ is produced, TCRβ is capable of pairing with pre-Tα to generate the pre-TCR, and that the pre-TCR can interact on the cell surface with the TCR signalling proteins.

Following β-selection thymocytes generate CD4+CD8+ double positive cells, which then undergo TCRα rearrangement, resulting in completely assembled TCR.

Positive selection and lineage commitment

A figure depicting the process of T cell / thymocyte positive and negative selection in the thymus Thymic selection.pdf
A figure depicting the process of T cell / thymocyte positive and negative selection in the thymus

Thymocytes which pass β-selection express a T cell receptor which is capable of assembling on the surface. However, many of these T cell receptors will still be non-functional, due to an inability to bind MHC. The next major stage of thymocyte development is positive selection, to keep only those thymocytes which have a T cell receptor capable of binding MHC. The T cell receptor requires CD8 as a coreceptor to bind to MHC class I, and CD4 as a coreceptor to bind MHC class II. At this stage thymocytes upregulate both CD4 and CD8, becoming double positive cells.

Double positive thymocytes that have a T cell receptor capable of binding MHC class I or class II (even with a weak affinity) receive signalling through the T cell receptor. [3] Thymocytes that have a T cell receptor incapable of binding MHC class I or class II undergo apoptosis. Some thymocytes are able to rescue failed positive selection by receptor editing (rearrangement of the other T cell receptor allele to produce a new T cell receptor).

The double positive thymocytes undergo lineage commitment, maturing into a CD8+ T cell (recognising MHC class I) or a CD4+ T cell (recognising MHC class II). Lineage commitment occurs at the late stage of positive selection and works by downregulation of both CD4 and CD8 (reducing the signal from the T cell receptor) and then upregulation of CD4 only. Thymocytes that start receiving signal again are those that recognise MHC class II, and they become CD4+ T cells. Thymocytes that do not start receiving signal again are those that recognize MHC class I, and they downregulate CD4 and upregulate CD8, to become CD8+ T cells. Both of these thymocytes types are known as single positive thymocytes.

Negative selection

Success in positive selection allows the thymocyte to undergo a number of maturational changes during the transition to a single positive T cell. The single positive T cells upregulate the chemokine receptor CCR7, causing migration from the cortex to the medulla. At this stage the key maturation process involves negative selection, the elimination of autoreactive thymocytes.

The key disadvantage in a gene rearrangement process for T cell receptors is that by random chance, some arrangements of gene fragments will create a T cell receptor capable of binding self-peptides presented on MHC class I or MHC class II. If T cells bearing these T cell receptors were to enter the periphery, they would be capable of activating an immune response against self, resulting in autoimmunity. Negative selection is the process evolved to reduce this risk. During negative selection, all thymocytes with a high affinity for binding self peptides presented on MHC class I or class II are induced to upregulate BCL2L11, a protein which drives apoptosis. Cells which do not have a high affinity for self-antigens survive negative selection. At this stage, some cells are also selected to become regulatory T cells, usually cells which have an intermediate affinity for self-peptide.

Negative selection can occur at the double positive stage in the cortex. However the repertoire of peptides in the cortex is limited to those expressed by epithelial cells, and double positive cells are poor at undergoing negative selection. Therefore, the most important site for negative selection is the medulla, once cells are at the single positive stage. In order to remove thymocytes reactive to peripheral organs, the transcription factors Aire and Fezf2 drive the expression of multiple peripheral antigens, such as insulin, resulting in deletion of cells specific for those antigens. [8] [9] This allows single positive thymocytes to be exposed to a more complex set of self-antigens than is present in the cortex, and therefore more efficiently deletes those T cells which are autoreactive.

Single positive thymocytes remain in the medulla for 1–2 weeks, surveying self-antigens to test for autoreactivity. During this time they undergo final maturational changes, and then exit the thymus using S1P and CCR7. Upon entry to the peripheral bloodstream, the cells are considered mature T cells, and not thymocytes.

Negative selection is not 100% effective, some autoreactive T cells escape thymic censorship, and are released into the circulation. Additional mechanisms of peripheral tolerance active in the periphery exist to silence these cells such as anergy, deletion, and regulatory T cells. If these peripheral tolerance mechanisms also fail, autoimmunity may arise.

Thymus transplantation results in that T cells are taught to avoid reacting with donor antigens instead, and may still react with many self-antigens in the body. Autoimmune disease is a frequent complication after thymus transplantation, found in 42% of subjects over 1 year post-transplantation. [10] However, this is partially explained by that the indication itself, that is, complete DiGeorge syndrome (absence of thymus), increases the risk of autoimmune disease. [11]

Cancer

Thymocytes that gain oncogenic mutations allowing uncontrolled proliferation can become thymic lymphomas.

Alternative lineages

As well as classical αβ T cells (their development of which is outlined above), a number of other T lineages develop in the thymus, including γδ T cells and Natural Killer T (NKT)cells. Additionally, other non-T hematopoietic lineages can develop in the thymus, including B lymphocytes (B cells), Natural Killer lymphocytes (NK cells). [12] [13] ), myeloid cells, and dendritic cells. However, the thymus is not a source of B, NKC, or myeloid development (this statement is not true for all B-cells or NKC). The development of these cells in the thymus reflects the multi-potent nature of hematopoietic progenitors that seed the thymus. Mature B-cells and other APCs can also be found in the medulla which contribute to negative selection processes. [14]

Related Research Articles

Thymus organ of the immune system

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts specifically to foreign invaders. The thymus is composed of two identical lobes and is located in the anterior superior mediastinum, in front of the heart and behind the sternum. Each lobe of the thymus can be divided into a central medulla and a peripheral cortex which is surrounded by an outer capsule.

T cell type of lymphocyte

A T cell is a type of lymphocyte, which develops in the thymus gland and plays a central role in the immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor on the cell surface. These immune cells originate as precursor cells, derived from bone marrow, and develop into several distinct types of T cells once they have migrated to the thymus gland. T cell differentiation continues even after they have left the thymus.

B cell Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. Additionally, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, and not from bone marrow as commonly believed.

Cytotoxic T cell T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell is a T lymphocyte that kills cancer cells, cells that are infected, or cells that are damaged in other ways.

The major histocompatibility complex (MHC) is a large locus on vertebrate's DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. This locus got its name because it was discovered in the study of tissue compatibility upon transplantation. Later studies revealed that tissues rejection due to incompatibility is an experimental artifact masking the real function of MHC molecules - binding an antigen derived from self-proteins or from pathogen and the antigen presentation on the cell surface for recognition by the appropriate T-cells. MHC molecules mediate interactions of leukocytes, also called white blood cells (WBCs), which are immune cells, with other leukocytes or with body cells. The MHC determines compatibility of donors for organ transplant, as well as one's susceptibility to an autoimmune disease via cross-reacting immunization.

Adaptive immune system subsystem of the overall immune system that is composed of highly specialized, systemic cells and processes that eliminate pathogens or prevent their growth

The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminates pathogens by preventing their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens, or from phagocytosed pathogens ; subsequent presentation of these antigens on class I or class II major histocompatibility complex (MHC) molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigen before they are stably expressed on a cell surface. MHC I antigen presentation typically involves the endogenous pathway of antigen processing, and MHC II antigen presentation involves the exogenous pathway of antigen processing. Cross-presentation involves parts of the exogenous and the endogenous pathways but ultimately involves the latter portion of the endogenous pathway.

T-cell receptor Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. 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.

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.

Lymphopoiesis (lĭm'fō-poi-ē'sĭs) is the generation of lymphocytes, one of the five types of white blood cell (WBC). It is more formally known as lymphoid hematopoiesis.

Minor histocompatibility antigen

Minor histocompatibility antigen are receptors on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. The proteins are composed of a single immunogenic HLA allele. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

T cell receptor gamma locus is a protein that in humans is encoded by the TRG gene, also known as TCRG or TRG@. It contributes the gamma (γ) chain to the larger TCR protein.

Harald von Boehmer German-Swiss immunologist

Harald von Boehmer was a German/Swiss immunologist best known for his work on T lymphocytes.

Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

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.

T-cell receptor revision is a process in the peripheral immune system which is used by mature T cells to alter their original antigenic specificity based on rearranged T cell receptors (TCR). This process can lead either to continuous appearance of potentially self-reactive T cells in the body, not controlled by the central tolerance mechanism in the thymus or better eliminate such self-reactive T cells on the other hand and thus contributing to peripheral tolerance - the extent of each has not been completely understood yet. This process occurs during follicular helper T cell formation in lymph node germinal centers.

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.

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 thymic epithelium within the thymic stroma. Thymus, as a primary lymphoid organ, mediates T cell development and maturation. 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 functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.

References

  1. " thymocyte " at Dorland's Medical Dictionary
  2. Figure 12-13 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN   978-1-4160-2973-1. 8th edition.
  3. 1 2 Baldwin TA, Hogquist KA, Jameson SC (2004). "The fourth way? Harnessing aggressive tendencies in the thymus". J Immunol. 173 (11): 6515–20. doi: 10.4049/jimmunol.173.11.6515 . PMID   15557139.CS1 maint: uses authors parameter (link)
  4. Schwarz BA, Bhandoola A. Trafficking from the bone marrow to the thymus: a prerequisite for thymopoiesis. Immunol Rev 209:47, 2006. full text
  5. Schwarz BA, Sambandam A, Maillard I, Harman BC, Love PE, Bhandoola A. Selective thymus settling regulated by cytokine and chemokine receptors. J Immunol. 2007 Feb 15;178(4):2008-17.
  6. C. Clare Blackburn & Nancy R. Manley "Developing a new paradigm for thymus organogenesis" Nature Reviews Immunology April 2004 278-289 Retrieved 10/4/12
  7. Sleckman BP, Lymphocyte antigen receptor gene assembly: multiple layers of regulation. Immunol Res 32:153-8, 2005. full text Archived 2008-01-27 at the Wayback Machine
  8. Anderson, M.S. et al. (2002) Projection of an Immunological Self-Shadow Within the Thymus by the Aire Protein. Science 298 (5597), 1395-1401
  9. Takaba, H. et al. (2015) Fezf2 Orchestrates a Thymic Programs of Self-Antigen Expression for Immune Tolerance. Cell 163, 975 - 987
  10. Thymus Transplantation Book Thymus Gland Pathology, pages 255-267, Springer Milan 2008 doi : 10.1007/978-88-470-0828-1 ISBN   978-88-470-0827-4 (Print) ISBN   978-88-470-0828-1 (Online) doi : 10.1007/978-88-470-0828-1_30
  11. Markert ML, Devlin BH, Alexieff MJ, et al. (May 2007). "Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants". Blood. 109 (10): 4539–47. doi:10.1182/blood-2006-10-048652. PMC   1885498 . PMID   17284531.
  12. van den Brandt J, Voss K, Schott M, Hünig T, Wolfe MS, Reichardt HM (May 2004). "Inhibition of Notch signaling biases rat thymocyte development towards the NK cell lineage". Eur. J. Immunol. 34 (5): 1405–13. doi:10.1002/eji.200324735. PMID   15114674.
  13. Sánchez MJ, Spits H, Lanier LL, Phillips JH (December 1993). "Human natural killer cell committed thymocytes and their relation to the T cell lineage". J. Exp. Med. 178 (6): 1857–66. doi:10.1084/jem.178.6.1857. PMC   2191276 . PMID   7504051.
  14. Geraldo A. Passos Cesar A. Speck‐Hernandez Amanda F. Assis Daniella A. Mendes‐da‐Cruz. "Update on Aire and thymic negative selection".Cite journal requires |journal= (help)