CHARMING SELECTION AND INEVITABLE DELETION OF T-CELLS
Updated: Feb 19, 2021
Today, Our main topic is development and clonal deletion of T lymphocytes. Well, Can this process be called as thymic education? Answer is totally yes... Exactly,scores of source names it like that. Thymic education is so essential point for regulating self-tolerance activity.
What did you say,could you please repeat it again? "Yeah,i said self-tolerance. This term is extremely important. It means that adaptive immunity is able to distinguish non-self from self. Self may be evaluated as our self-antigens,cells etc. Thus , every pathogenic condition that may exist in human body can be detected by immune cells,especially adaptive immune cells which include T and B lymphocytes. But right now, we will concentrate on only T-cells.
As i said before,Main concept is T-cell development and clonal deletion...
Let's get started with brief information before the enterance of main topic!
Human being has two types immune response which are innate plus adaptive or acquired immunities —image 1—. Innate immunity does not give any specific response to pathogens. It is so basic but so important concept of immunity. Adaptive immunity is special for just vertebrates. We can not see any adaptive response in organisms that have more low-lvl evolutionary characters than vertebrates have.
Image 1 : is taken from Abbas Cellular and Molecular Immunology 2018 ed.
Let's look at adaptive immunity and its features!
As you know that , Cells that belong to immune system are produced in bone marrow. Production areas change with gestational term and age.— image2—
Image2: is taken from Juncuiera's Basic Histology 14th ed.
Hematopoetic stem cells like other stem cells have self-renewal and differentiation features in its activity. They are located in bone marrow. Related cell production process includes two lineages. These are myeloid and lymphoid lineages. Right now,lymphoid lineage is significant point for us.—image 3— Because it gives us related cells that we are interested in.
Image 3: is taken from Ganong's Physiology 23rd ed.
Maturation of B cells are completed in bone marrow. But T cell maturation depends on thymic education and T cells have to migrate to the thymus for maturation.
T-cell tolerance prevents unwanted or self-reactive immune responses. So that , Human body can stay unresponsive to self antigens and can attack foreign matters effectively. There are three types T-cells. These are cytotoxic T-cells , helper T-cells and regulatory T-cells:
CYTOTOXIC T LYMPHOCYTES : Every cytotoxic T cell is distinguished by copies of its own unique TCR as well as the presence of CD8 cell surface glycoproteins. For this reason , cytotoxic T cells are also known as CD8 positive cells. As the name implies , these lymphocytes directly kill other cells such as those infected with viruses or other intracellular pathways. They can also kill abnormal cells such as cancer cells.
HELPER T LYMPHOCYTES : Immunologists distinguish helper T cells, by the presence of CD4 glycoproteins in the cell's cytoplasmic membranes so Th cells are also called CD4 positive cells. These cells are named helpers because their function is to help regulate the activity of B cells and cytotoxic T cells during immune responses by providing neccessary signals and growth factors.
REGULATORY T LYMPHOCYTES : Immunologists recognize regulatory T cells by the presence of both CD4 and CD25 glycoproteins. These cells generally suppress immune responses and promote tolerance of certain antigens.
Image 4 : is taken by Abbas Cellular and Molecular Immunology 2018 ed.
After all of basic knowledges , We can concentrate on our main topic!
Clonal deletion : A mechanism of lymphocyte tolerance in which an immature T cell in the thymus or an immature B cell in the bone marrow undergoes apoptotic death as a consequence of recognizing a self-antigen.
Positive selection : T cells recognize antigenic peptides only when presented by self-MHC molecules on APCs. If effect, T cells show "dual recognition" of both the antigenic peptides and the polymorphic part of the MHC molecules. (CD4, found on some subsets of Tells, also attaches to the class II molecules, but to the non-polymorphic portion). Positive selection (also called thymic education) ensures that only those TCRs with a moderate affinity for self-MHC are allowed to develop further. There is evidence that positive selection is mediated through thymic epithelial cells, acting as APCs. T cells displaying very high or very low receptors affinity for self-MHC undergo apoptosis and die in the cortex. Apoptosis is a pre-programmed "suicide" achieved by activating endogenous nucleases that cause DNA fragmentation.
Negative Selection : Some of the positively selected T cells may have receptors that recognize self components other that n self- MHC. These cells are deleted by a "negative selection" process, which occurs in the deeper cortex at the corticomedullary junction and in the medulla. The thymocytes interact with antigen, interdigitating cells and macrophages. Only thymocytes that fail to recognize self antigen are allowed to proceed. The rest undergo apoptosis and are destroyed. These, and all the other apoptotic cells generated in the thymus, are phagocytosed by tangible body macrophages in the deep cortex. The existence of negative selection (also called central tolerance) has recently received strong experimental support from murine studies in which specific Vβ families are eliminated by certain endogenous superantigens during thymic development.
T cell at this stage of maturation (CD4+ or CD8+ TCRlo) go on to express TCR at high density and lose either CD4 or CD8, becoming "single positive" mature thymocytes. These separate subsets of CD4+ and CD8+ cells possess specialized homing receptors, and exit to the T-cell areas of the peripheral lymphoid tissues where they function primarily as mature "helper" and cytotoxic" T cells respectively. Fewer than 5% of thymocytes leave the thymus. The rest die as the result of selection processes and failure to express antigen receptors.
Image 5 : is taken from mlinjawi.kau
T-cell differentiation and negative and positive selection in the thymus, in this model pre- thymic T cells are attracted to and enter the thymic rudiment. They proliferate below the subcapsular region as large lymphoblast, which replicate and give rise to a pool of cells entering the differentiation pathway. Many of these cells are associated with epithelial thymic nurse cells (TNCs), although the significance of this interaction is still debated. Cells in this region first acquire jCD8 and then CD4 at low density. They also re-arrange their TCR genes and may express the products of these genes at low density on the cell surface > maturing cells move deeper into the cortex and adhere to cortical epithelial cells. These epithelial cells are elongated and branched, and thus provide a large surface area for contact with thymocytes. The TCRs on the thymocytes are exposed to epithelial MHC molecules through these contacts. This leads to positive selection. Those cells which are not selected undergo apoptosis and are phagocytosed by macrophages. There is an increased expression of CD3 TCR, CD4, and CD8 during thymocyte migration from the subcapsular region to the deeper cortex. Those TCRs with self reactivity are now deleted through contact with autoantigens presented by interdigitating cells and macrophages at corticomedullary junction0 a process called negative selection. Medullary epithelial cells might also contribute to this process. Following this stage, cells expressing either jCD4 or CD8 appear and exit to the periphery via specialized vessels at the corticomedullary junction. (A process of negative selection may also occur in the cortex, leading to the elimination of cells whose TCRs have high affinity for self MHC. The generation of the T cell repertoire by the process of genre rearrangement and recombination is random. Since TCRs can only recognize antigenic peptide associated with MHC and presented by an antigen-presenting cell (APC), the selection for functional TCRs is dependent on the type of MHC expressed on APC. These arguments lay the foundation for the concept of MHC restriction.(1)
MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) RESTRICTION
It has been proven that when T cells from stain A mice are given a choice to react with foreign antigen presented on APC of strain A or B, they will preferentially react with strain A APC and therefore are restricted by MHC type A. The concept of MHC restriction further separates the antigen recognition specificity of TCR expressed on T cells from the Ig expressed by B cells, whose ability to bind antigen does not require MHC restriction. In general, mature CD4 T cells are selected by MHC class II, while mature CD8 T cells are selected by MHC class I on the cortical thymic epithelium. Thus, MHC expressed by cortical thymic epithelium dictates the specificity of the positively selected TCR.
Attention please! This point is breathtaking aspect...
One of the most intriguing aspects of negative selection is that it primarily occurs in the thymus, which means that T cells rely solely on the cells in the thymus to present self-peptides on MHC molecules. Because of this, it is tempting to think that negative selection will only delete T cells who show reactivity to thymic self-peptides… but what about peptide-MHC complexes specific to the stomach or the skin or the lungs? Would the T cells that survive negative selection leave the thymus only to kill cells of our other organs? Clearly, this is not the case, and the reason is attributed to a protein called autoimmune regulator, or AIRE. The role of AIRE in the thymus is to induce the expression of many proteins that are not typically expressed in thymic cells, such as proteins characteristic of the lungs. In this way, developing T cells are exposed to many peptide-MHC complexes, not just those normally expressed by thymic cells, thereby preventing autoimmunity once T cells leave the thymus.(2)
Finally We have a lot of questions that need to be answered...My dear readers,
Stay with science!
Image 6 : is taken from immunobites.com
Image 7 : is taken from Pearson Microbiology with Diseases by Body System 2019 ed.
Abbas Cellular and Molecular Immunology 2018 ed.
Ganong's Physiology 23rd ed.
Pearson Microbiology with Diseases by Body System 2019 ed.
Junqueira's Basic Histology 14th ed.