Clonal deletion

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In immunology, clonal deletion is the process of removing T and B lymphocytes from the immune system repertoire. [1] [2] 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. [3] 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.

Contents

Discovery

Central tolerance and clonal deletion did not get much attention in the early years of immunology. [2] [4] Frank Macfarlane Burnet was the first to suggest the idea of clonal deletion. A couple key findings helped Burnet's in this discovery. In 1936, Erich Traub demonstrated that when a developing mouse in the uterus is infected with a virus, once it is born it will elicit no antibody response to that same virus. Whereas a mouse that develops normally with no viral introduction during development, will develop an immune response to the same virus when infected after birth. [5] [6] Then in 1945, Ray David Owens observed that the that non-identical cattle twins were unable to reject blood from one another when the cattle had different blood types. [4] [5] The combination of Traub's evidence and Owens' observations helped Burnet and his partner, Frank Fenner, to propose that 'self' markers for host cells were determined at an embryonic state. [5] Burnet was then able to hypothesize, in 1959, the clonal selection hypothesis. [2] [5] In part of this hypothesis, Burnet stated that an auto-reactive lymphocyte would be terminated before maturation in order to prevent further proliferation. [2] [7] Burnet, and others, would then go on to win the Nobel Prize in 1960 for their contributions to immunological tolerance. [4] Now, clonal deletion has been a broadly discussed topic in immunology and transplantation for the past decades. [5]

Function

A visual representation of the process of clonal deletion in the primary lymphoid organs Clonal Deletion.png
A visual representation of the process of clonal deletion in the primary lymphoid organs

There are millions of B and T lymphocytes within the immune system. As a T or B lymphocyte develops, they can rearrange their genome in order to express a unique antigen that will recognize a specific epitope on a pathogen. [8] [9] There is a large diversity of epitopes recognized and, as a result, it is possible for some B and T lymphocytes to develop with the ability to recognize self. [10] In order to prevent this from happening, every T and B lymphocyte that is generated is presented with a self antigen. [2] [7] If the antigen receptor present on the lymphocyte interacts with high affinity to the self antigen, then that that lymphocyte is then categorized as 'self-reactive'. These 'self-reactive' lymphocytes will then undergo the process of clonal deletion. This is achieved through apoptosis of the respected cell, ultimately deleting the cell from the immune system. [2] It is important to note that not all lymphocytes expressing high affinity for self-antigen undergo clonal deletion. If autoreactive cells escape clonal deletion, there are mechanisms in the periphery involving T regulatory cells to prevent the host from obtaining an autoimmune disease. [7] However, for both B and T cells in the primary lymphoid organs, clonal deletion is the most common form of negative selection. The process of clonal deletion helps protect the host from autoimmunity. [2] [7]

Location and Mechanism

B and T lymphocytes are tested for self reactivity in the primary lymphoid organs, before entering into the periphery. [2] The site at which this occurs is dependent on the type of lymphocyte. [8] B lymphocytes both develop and mature within the bone marrow. Whereas T lymphocytes develop in the bone marrow and mature later in the thymus, hence the T. [8] The mechanisms of central tolerance are not completely affective, and some autoreactive lymphocytes can find their way into circulation. However, the immune system has secondary defenses within the periphery to protect against this, referred to as peripheral tolerance. [11] [12]

B Lymphocytes

Regulation of auto-reactive B lymphocytes can occur at many different stages during B cell development. The first line of defense occurs within the bone marrow, before the auto-reactive cell can reach circulation. [8] [11] This occurs after the functional B-cell receptor (BCR) is assembled. [3] If the BCR demonstrates a high affinity attraction to self-antigen then clonal deletion can occur at this point. However, some auto-reactive B lymphocytes can slip through this check point and find their way into circulation. If this occurs, then this is when peripheral tolerance come into affect. This is the process of removing auto-reactive cells within circulation after they have fully-matured. Examples of mechanisms used in peripheral tolerance against auto-reactive B lymphocytes include anergy, and antigen receptor desensitization. Like central tolerance, peripheral tolerance is not always fully accurate, leaving the possibility for an auto-reactive lymphocyte to remain in circulation. [11]

T Lymphocytes

The process of removing auto-reactive T lymphocytes occurs in the thymus. [2] [8] [12] The thymus contains two zones: the outer region called the thymic cortex, and the inner region called the thymic medulla. Within these regions T lymphocytes will undergo a series of positive or negative selection. [12] [13]

Thymic cortex

T lymphocytes first undergo positive selection within the thymic cortex. Here T lymphocytes are tested to see if they can recognize self major histocompatibility complex class I or II (MHC I/II). [12] If the T lymphocyte can recognize self MHC I/II then it will continue maturation and move into the thymic medulla. If the T lymphocyte cannot recognize self (MHC I/II) then it will undergo neglect or apoptosis. [13] Thymic dendritic cells and macrophages appear to be responsible for the apoptotic signals sent to autoreactive T cells in the thymic cortex. [3] [14]

Thymic medulla

T cells also have the opportunity to undergo clonal deletion within the thymic medulla. Here the T lymphocytes undergo negative selection. [12] [13] At this point they encounter MHC I/II complexes presenting self antigens. [12] If the T lymphocyte interacts with high affinity to the complex presenting self antigen, then that lymphocyte will undergo apoptosis or Treg differentiation. [13] Similarly to B lymphocyte regulation, T lymphocytes have the potential to leave the thymus and still be autoreactive. However, the immune system has evolved to combat this though peripheral tolerance. Mechanisms of peripheral tolerance against auto-reactive T lymphocytes include clonal arrest, clonal anergy, and clonal editing after. [3]

Complete vs. incomplete clonal deletion

A visual representation of incomplete and complete clonal deletion Incomplete vs. Complete Clonal Deletion.png
A visual representation of incomplete and complete clonal deletion

Complete clonal deletion results in apoptosis of all B and T lymphocytes expressing high affinity for self antigen. [2] Incomplete clonal deletion results in apoptosis of most autoreactive B and T lymphocytes. [2] Complete clonal deletion can lead to opportunities for molecular mimicry, which has adverse effects for the host. [2] Therefore, incomplete clonal deletion allows for a balance between the host’s ability to recognize foreign antigens and self antigens. [2]

Methods of exploitation

Molecular mimicry

Clonal deletion provides an incentive for microorganisms to develop epitopes similar to proteins found within the host. Because most autoresponsive cells undergo clonal deletion, this allows microorganisms with epitopes similar to host antigen to escape recognition and detection by T and B lymphocytes. [2] However, if detected, this can lead to an autoimmune response because of the similarity of the epitopes on the microorganism and host antigen. Examples of this are seen in Streptococcus pyogenes and Borrelia burgdorferi. [2] It is possible, but uncommon for molecular mimicry to lead to an autoimmune disease. [2]

Superantigens

Superantigens are composed of viral or bacterial proteins and can hijack the clonal deletion process when expressed in the thymus because they resemble the T-cell receptor (TCR) interaction with self MHC/peptides. [1] Thus, through this process, superantigens can effectively prevent maturation of cognate T cells.

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<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">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

<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.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

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.

Molecular mimicry is the theoretical possibility that sequence similarities between foreign and self-peptides are enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the prevalence of several peptide sequences which can be both foreign and self in nature, just a few crucial residues can activate a single antibody or TCR. This highlights the importance of structural homology in the theory of molecular mimicry. Upon activation, these "peptide mimic" specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity). Molecular mimicry is one of several ways in which autoimmunity can be evoked. A molecular mimicking event is more than an epiphenomenon despite its low probability, and these events have serious implications in the onset of many human autoimmune disorders.

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.

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">Harald von Boehmer</span> German-Swiss immunologist

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

In immunology, cryptic self epitopes are a source of autoimmunity.

Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.

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.

<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.

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.

In the immune system, veto cells are white blood cells that have a selective immunomodulation properties. Veto cells were first described in 1979 as cells that “can prevent generation of cytotoxic lymphocytes by normal spleen cells against self-antigens”. Hence, veto cells delete T cells that recognize the veto cells.

References

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  5. 1 2 3 4 5 Hall, B. M., Verma, N. D., Tran, G. T., & Hodgkinson, S. J. (2022). Transplant Tolerance, Not Only Clonal Deletion. Frontiers in immunology, 13, 810798. https://doi.org/10.3389/fimmu.2022.810798
  6. ↑ Traub E. (1936). AN EPIDEMIC IN A MOUSE COLONY DUE TO THE VIRUS OF ACUTE LYMPHOCYTIC CHORIOMENINGITIS. The Journal of experimental medicine, 63(4), 533–546. https://doi.org/10.1084/jem.63.4.533
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  9. ↑ Charles A Janeway, Jr; Travers, Paul; Walport, Mark; Shlomchik, Mark J. (2001), "The rearrangement of antigen-receptor gene segments controls lymphocyte development", Immunobiology: The Immune System in Health and Disease. 5th edition, Garland Science, retrieved 2024-04-23
  10. ↑ Kitz, Alexandra; Hafler, David A. (2015). "Thymic Selection: To Thine Own Self Be True". Immunity. 42 (5): 788–789. doi:10.1016/j.immuni.2015.05.007. PMID 25992854.
  11. 1 2 3 Nemazee D. (2017). Mechanisms of central tolerance for B cells. Nature reviews. Immunology, 17(5), 281–294. https://doi.org/10.1038/nri.2017.19
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  14. ↑ Klein, Ludger; Kyewski, Bruno; Allen, Paul M.; Hogquist, Kristin A. (2014). "Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)". Nature Reviews Immunology. 14 (6): 377–391. doi:10.1038/nri3667. PMC 4757912. PMID 24830344.
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