- T lymphocytes (T cells, named for their formation in the thymus) are essential components of the adaptive immune system.
- It is directly engaged in the destruction of infected host cells, the production of cytokines, the activation of other immune cells, and the regulation of the immune response.
- These cells are crucial to the immunological response. T-cells can be distinguished from other lymphocytes due to the presence of t-cell receptors on the cell surface.
- Once they reach the thymus gland, the precursor cells from the bone marrow that gave rise to these cells undergo additional development into various types of T cells. Although T cells have left the thymus, they continue to differentiate.
What is T cell (T Lymphocyte)?
- T cells are a kind of lymphocyte. T cells are a vital component of the adaptive immune response and one of the most significant white blood cells of the immune system.
- On the cell surface of T cells is a T-cell receptor (TCR), which distinguishes them from other lymphocytes.
- Hematopoietic stem cells, located in the bone marrow, give rise to T lymphocytes. Developing T cells travel to the thymus gland where they mature (or mature).
- The thymus provides the nomenclature for T lymphocytes. After migrating to the thymus, the precursor cells mature into a variety of T cell subtypes.
- T cells continue to differentiate after they leave the thymus. Specific subtypes of differentiated T cells have a number of crucial roles in regulating and directing the immune response.
- Two major subtypes, CD8+ “killer” and CD4+ “helper” T cells, carry out one of these activities, immune-mediated cell death. (They are named for the cell surface proteins CD8 and CD4 they contain.)
- CD8+ T cells, commonly known as “killer T cells,” are cytotoxic, meaning they are capable of directly killing virus-infected and cancerous cells.
- When developing an immune response, CD8+ T cells can also utilise tiny signalling proteins known as cytokines to recruit other cell types. CD4+ T cells, a distinct group of T cells, serve as “helper cells.”
- CD4+ helper T (TH) cells, unlike CD8+ killer T cells, work by activating memory B cells and cytotoxic T cells, resulting in a bigger immune response.
- The unique adaptive immune response regulated by TH cells depends on their cytokine-secreting subtypes.
- Regulatory T cells are yet another separate population of T cells that provide the essential tolerance mechanism by which immune cells are able to discriminate invading cells from “self” cells.
- This stops immune cells from reacting incorrectly against a person’s own cells, which is known as a “autoimmune” reaction. Because of this, regulatory T cells are also known as suppressor T cells.
- These regulatory T cells can also be co-opted by cancer cells to hinder the immune system from recognising and attacking tumour cells.
Types of T cell (T Lymphocyte)
A. Conventional adaptive T cells
1. Helper CD4+ T cells
- T helper cells (TH cells) support the maturation of B cells into plasma cells and memory B cells, as well as the activation of cytotoxic T cells and macrophages.
- These cells are also known as CD4+ T cells because their surfaces express the CD4 glycoprotein.
- Helper T cells become activated when peptide antigens are delivered to them by MHC class II molecules on the surface of antigen-presenting cells (APCs).
- Once triggered, these cells proliferate rapidly and release cytokines that regulate or support the immune response.
- These cells can develop into various subtypes with distinct functions. Cytokines guide T cells toward specific subtypes.
CD4+ Helper T cell subsets
- Th1: Generate an inflammatory response, which is essential for protection against intracellular bacteria, viruses, and cancer. (Related diseases: Multiple Sclerosis and Type 1 diabetes)
- Th2: Immunologically significant against external pathogens, such as worm infections, that are Th2 cells. (Asthma and other allergy illnesses are related)
- Th17: Protection against intestinal pathogens and mucosal barriers. (Related diseases: Multiple Sclerosis, Rheumatoid Arthritis, and Psoriasis)
- Th9: Protection against parasitic helminths and cell-dependent allergic inflammation. Multiple Sclerosis is a related condition.
- Tfh: Aid B cells in producing antibodies.
- (Asthma and other allergy illnesses are related)
- Th22: Pathogenesis of allergic airway disorders is primarily anti-inflammatory, according to Hypothesis 22. (Related diseases: Crohn’s, Rheumatoid, and Tumors)
2. Cytotoxic CD8+ T cells
- Cytotoxic T cells (TC cells, CTLs, T-killer cells, killer T cells) are responsible for the destruction of virus-infected and tumour cells, as well as transplant rejection.
- The expression of the CD8 protein on the surface of these cells defines them. Cytotoxic T cells recognise their targets by attaching to short peptides (8 to 11 amino acids) associated with MHC class I molecules, which are found on the surface of all nucleated cells.
- IL-2 and IFNγ are two essential cytokines produced by cytotoxic T cells. These cytokines have an effect on the effector activities of other cells, particularly macrophages and NK cells.
3. Memory T cells
- After encountering their relevant antigen in the context of an MHC molecule on the surface of a professional antigen-presenting cell, antigen-naive T cells proliferate and develop into memory and effector T cells (e.g. a dendritic cell).
- For this mechanism to occur, appropriate co-stimulation must be present at the time of antigen contact.
- Historically, it was believed that memory T cells belonged to either the effector or central memory subtypes, each having a unique set of cell surface markers (see below).
- Numerous other populations of memory T cells, including tissue-resident memory T (Trm) cells, stem memory TSCM cells, and virtual memory T cells, were subsequently found.
- Upon re-exposure to their associated antigen, all subtypes of memory T cells rapidly proliferate into huge numbers of effector T cells and have a lengthy life span.
- Through this method, they impart “memory” to the immune system against previously encountered infections. Memory T cells are typically CD4+ or CD8+ and CD45RO-positive.
Memory T cell subtypes
- Central memory T cells (TCM cells): Central memory T cells (TCM cells) are characterised by the expression of CD45RO, C-C chemokine receptor type 7 (CCR7), and L-selectin (CD62L). CD44 expression is intermediate to high in central memory T cells. This subset of memory cells is typically observed in lymph nodes and peripheral circulation. (Note that CD44 expression is typically utilised to differentiate between murine naïve and memory T cells)
- Effector memory T cells (TEM cells and TEMRA cells): They also exhibit moderate to high CD44 expression. Lacking lymph node-homing receptors, these memory T cells are located in the peripheral circulation and tissues. TEMRA is the abbreviation for terminally developed effector memory cells that re-express CD45RA, a typical marker for naïve T cells.
- Tissue-resident memory T cells (TRM): Tissue-resident memory T cells (TRM) do not recirculate and occupy tissues (skin, lung, etc.). The intern e7, commonly known as CD103, is a cell surface marker that has been linked to TRM.
- Virtual memory T cells (TVM): Virtual memory T cells (TVM) vary from other memory subsets in that they do not arise from a clonal expansion event. Individual virtual memory T cell clones reside at relatively low frequencies, despite the fact that this population as a whole is plentiful in the peripheral circulation. The origin of this T cell population, according to one idea, is homeostatic proliferation. Although CD8 virtual memory T cells were initially identified, it is now understood that CD4 virtual memory T cells also exist.
4. Regulatory CD4+ T cells
- Regulatory T cells are crucial for maintaining immunological tolerance. Their primary function is to shut down T cell-mediated immunity after the conclusion of an immune response and to inhibit autoreactive T cells that evaded thymic negative selection.
- Two major kinds of CD4+ Treg cells have been described—FOXP3+ Treg cells and FOXP3− Treg cells.
- Regulatory T cells can either develop normally in the thymus, in which case they are known as thymic Treg cells, or they can be induced peripherally, in which case they are known as peripherally derived Treg cells.
- These two subsets were formerly dubbed “naturally occurring” and “adaptive” (or “induced”), respectively.
- The expression of the transcription factor FOXP3, which can be utilised to identify the cells, is required for both subsets. Mutations of the FOXP3 gene can impair regulatory T cell development, leading the deadly autoimmune illness IPEX.
- Several other types of T cells exhibit suppressive function, but do not constitutively express FOXP3. These include Tr1 and Th3 cells, which are hypothesised to arise during an immune response and act by generating suppressive chemicals.
- IL-10 is connected with Tr1 cells, while TGF-beta is associated with Th3 cells. Th17 cells were just added to this list.
B. Innate-like T cells
- Unconventional or innate-like T cells are subsets of T cells that behave differently during immunity.
- In contrast to their traditional counterparts (CD4 T helper cells and CD8 cytotoxic T cells), which are dependent on the identification of peptide antigens in the context of the MHC molecule, they induce fast immune responses regardless of MHC expression.
- NKT cells, MAIT cells, and gammadelta T cells comprise the three largest groups of unconventional T cells. Now, their functional roles in the context of infections and cancer are well-established.
- In addition, these T cell subsets are being translated into a variety of treatments for cancers, such as leukaemia.
Natural killer T cell
- NKT cells connect the adaptive immune system to the innate immune system.
- NKT cells identify glycolipid antigens presented by CD1d, in contrast to typical T cells, which recognise protein peptide antigens presented by major histocompatibility complex (MHC) molecules.
- Once activated, these cells can perform both helper and cytotoxic T cell tasks, including cytokine production and the release of cytolytic/cell-killing chemicals.
- They can also identify and kill some tumour cells and herpes virus-infected cells.
Mucosal associated invariant T cells
- Mucosal associated invariant T (MAIT) cells have innate effector-like characteristics. MAIT cells are present in the blood, liver, lungs, and mucosa of humans, where they guard against microbial activity and infection.
- The MHC class I-like protein MR1 is responsible for delivering vitamin B metabolites generated by bacteria to MAIT cells.
- MAIT cells are capable of lysing bacterially infected cells upon the presentation of foreign antigen by MR1.
- MAIT cells can potentially be triggered via signalling independent of MR1.
- In addition to exhibiting innate-like activities, this subgroup of T cells possesses a memory-like phenotype and supports the adaptive immune response.
- In addition, it is believed that MAIT cells play a role in autoimmune disorders such as multiple sclerosis, arthritis, and inflammatory bowel disease, although definitive proof has not yet been published.
Gamma delta T cells
- Gamma delta T cells ( γδ T cells) are a small group of T cells that have a γδTCR on the cell surface instead of a αβTCR. A large number of T cells have αβ TCR chains.
- This group of T cells makes up only about 2% of all T cells in humans and mice. They are mostly found in the gut mucosa, where they are part of a group of intraepithelial lymphocytes.
- γδT cells can make up as much as 60% of all T cells in rabbits, sheep, and chickens. Most of what we know about the antigenic molecules that turn on γδ T cells is still pretty new. But γδ T cells are not limited by MHC and seem to be able to recognise whole proteins without the need for MHC molecules on APCs to present peptides.
- Some murine γδT cells can recognise molecules called MHC class IB. Most of the γδ T cells in the peripheral blood of humans are those that use the Vγ9 and Vδ2 gene fragments.
- These cells are unique because they respond quickly and specifically to a group of nonpeptidic phosphorylated isoprenoid precursors called phosphoantigens. Almost all living cells make phosphoantigens.
- Isopentenyl pyrophosphate (IPP) and its isomer, dimethylallyl pyrophosphate, are found in most animal and human cells, including cancer cells (DMPP).
- Along with IPP and DMAPP, many microbes also make the active compound hydroxy-DMAPP (HMB-PP) and the corresponding mononucleotide conjugates. Both types of phosphoantigens are made by plant cells.
- Human Vγ9/Vδ2 T cells can be turned on by drugs that contain synthetic phosphoantigens and aminobisphosphonates, which turn on the body’s own IPP/DMAPP.
The T Cell Receptor
- The T cell receptor (TCR) is a transmembrane heterodimer made up of two polypeptide chains that are linked by disulfide bonds.
- Each lymphocyte has a TCR that is only good for one thing. Antigens can cause T lymphocytes to divide and make copies of themselves with the same antigenic specificity.
- Alpha (α) and beta (β) chains are found on the outside of almost all T lymphocytes.
- Only 5% of a healthy adult’s normal T cell population is made up of cells that have gamma (γ) and delta (δ) chains.
- Each chain (α, β, γ, or δ) is a different protein with an approx. 45 kDa molecular weight. As its receptor, a T cell can have either a heterodimer αβ or a γδ a heterodimer, but never both.
- The TCR is always expressed with the related CD3 complex, which is made up of multiple units that can be expressed on their own and is needed for signal transduction once antigen is presented.
Development of T Cells
- The common lymphoid progenitor cell is the precursor of all lymphoid cells and develops from hematopoietic stem cells in the bone marrow. Precursors of T cells travel to the thymus, where they mature and are weeded out based on their ability to destroy other T cells (thymic selection).
- Gene rearrangements that occur during T cell development, like those that occur during the development of B cells, lead to TCR-specific T cells.
- V(D)J recombination describes the process by which the TCR gene gets rearranged. Recombination events of certain genes in the V (variable), D (diversity), and/or J (joining) regions occur in the germ line sequences of developing T cells.
- In the same way that B cells can undergo N region diversification by inserting more nucleotides via the enzyme deoxynucleotidyl transferase, the pool of TCRs that can be created can also be increased.
- During childhood and adolescence, the thymus produces the greatest numbers of T cells. Thymus atrophy in adulthood suggests that the full set of T cells is mostly determined before reaching puberty.
- T cell lineage development begins in the thymic cortex and concludes in the thymic medulla, and the thymus plays an important role in both training and regulation of this lineage.
- The predominant CD4 and CD8 markers are not expressed by progenitor cells throughout their migration to the thymus. We refer to these progenitor cells as “double-negative” thymocytes because of this characteristic. Rearrangement of the T cell receptor (TCR) is an important developmental stage that results in a cell’s definitive commitment to either the αβ T cell or γδ T cell phenotype.
- Like B cells, T lymphocytes are predisposed to respond to a wide variety of antigens. Recombination occurs during the process of TCR gene rearrangement.
- A functioning TCR must be expressed by the developing cells. CD3 molecule expression at this time permits intracellular signal transmission. Proliferation and expression of CD4 and CD8 cells are triggered by this signalling.
- Double-positive thymocytes is the current terminology for these cells. The process of selection that ultimately forms the T cell repertoire starts when the whole αβ TCR is expressed on the surface of thymocyte cells.
- Antigen presentation via the major histocompatibility complex is essential for T cell recognition of antigen, but T cells must also recognise the peptide epitope that is being presented (MHC).
- First, positive selection takes place, and the developing αβ TCR that detects both MHC and the peptide epitope is permitted to flourish. The maturation of CD4 and CD8 T cells is timed to coincide with the positive recognition of MHC class I or class II.
- A thymocyte that identifies MHC class I will stop expressing CD4, resulting in the formation of a CD8 T cell, and vice versa.
- At the conclusion of positive selection, the cell becomes a monoclonal positive thymocyte with elevated αβ TCR expression.
- Next, the cells are put through a negative selection process in which they are examined for their ability to respond to selfantigens. Those that make it to adulthood complete the maturation process and are released into the population.
Positive Selection of T Cells
- Two-times-positive ab TCR Before leaving the thymus, low cells must first pass through positive and negative selection. When cells that have successfully altered their ab TCR fail to attach self MHC within 3-4 days, they perish in the thymus cortex.
- By binding cortical epithelial cells expressing Class I or Class II MHC plus self peptides with sufficient affinity, double-positive T cells undergo positive selection and are given the go-ahead to survive.
- Apoptosis is triggered in double-positive T cells when they attach to antigen-presenting cells (APCs; macrophages and dendritic cells) originating from bone marrow that express Class I or Class II MHC plus self peptides.
- In the absence of a pathogen, MHC presents self peptides in the thymus, where selection takes place.
- In radiation chimaeras, or bone marrow chimaeras, animals with their hematopoietic cells damaged by irradiation had hematopoietic cells from another mouse strain transplanted into their bone marrow.
- F1 an x b mice, the offspring of an MHCa parent and an MHCb parent, had their bone marrow harvested because the cells contained both MHCa and MHCb alleles. Since an x b mouse T cells are MHC restricted, they will only respond to antigen presented on MHCa or MHCb.
- Radiation-treated mice were either MHCa or MHCb recipients. Although they lacked hematopoietic cells, they did contain a thymic stroma that could perform its role. In the thymus of the recipient, cells from the an x b donor’s bone marrow matured into APC, B cells, and T cells.
- T cells recognised antigen presented solely on APC of the host MHC type (MHCA in MHCa receivers and MHCb in MHCb recipients), despite the fact that both the T cells and the APC were an x b cells. This can be shown experimentally by exposing T cells to antigen-presenting cells (APC) expressing either MHC-a or MHC-b.
- Thus, the thymic epithelial cells had positively chosen the T cells to recognise host MHC.
- One more experiment in an MHCa x b thymectomized mouse verified the positive selection of T cells on thymic stroma. The thymus was excised at an early age and replaced with an MHCa thymus and MHCaxb bone marrow cells in a mouse that had previously had its thymus surgically removed.
- A x B cells nevertheless remained MHCa restricted, and could only respond to foreign antigen presented on MHCa APC, even when the only MHCa cells in the mice were thymic stromal cells. Therefore, “self” MHC for growing T cells is determined by thymic epithelial stromal cells.
- The MHCb-restricted T cells generated when MHCa bone marrow cells were injected into MHCb animals were unable to respond to foreign antigen in the host mice because all the APC were also derived from the MHCa bone marrow cells.
- Based on the results of this study, it is clear that the immune system can only operate properly if the bone marrow donor and recipient share at least one MHC allele. Given the significance of human bone marrow transplantation, this is an essential factor to take into account.
- T cell maturation requires recognition of self MHC on the thymic epithelium, as shown by transgenic mice for TCR limited to a known MHC allele.
- Keep in mind that growing T cells will display the transgenic a and b chains of TCR since lymphoid progenitors with rearranged TCR transgenes genes will not rearrange their own (endogenous) TCR genes.
- The inability of transgenic T cells to become single positive T cells and die in the thymus was demonstrated by flow cytometry using antibodies to the transgenic TCR (called clonotypic antibodies since they are specific for the TCR idiotype), as well as antibodies to CD4 and CD8.
- The more a chain rearrangements a growing T cell is able to make, the better its chances of being subjected to positive selection. About one-third of T cells are found to express several TCRs.
- T cells with two TCR idiotypes should still have just one idiotype that can identify peptide on self MHC and not violate clonal selection because the chance of positive selection is limited.
- Genes for both MHC alleles and TCRs are passed down separately. However, it appears that all regions of the TCR V gene (including CDR1 and CDR 2 that engage MHC) are capable of binding some MHC alleles, hence increasing the likelihood of positive selection.
- The fate of a T cell, whether it develops into a helper or cytotoxic T cell, is also decided by positive selection. CD8 Tc cells are the result of positive selection on Class I MHC, while CD4 Th cells are the result of positive selection on Class II MHC.
- TCR transgenic mice, which are able to bind Class I or Class II MHC, provide more proof of this. Class I TCR transgenic animals produce only Tc cells, and Class II TCR transgenic mice produce only Th cells.
- Transgenic mice that only manufacture Class II on their thymic epithelial cells yield normal quantities of CD4 T cells, while mice who cannot express Class II MHC generate only CD8 T cells.
- Similarly, Tc cell production is blocked in animals with a TAP mutation because they are unable to present peptide on Class I MHC, and in mice with no DM because they are unable to present peptide on Class II MHC.
- Bare lymphocyte syndrome is an immunodeficiency in humans that manifests as a lack of MHC expression and an inability to generate the matching T cell type. Positive selection also requires the expression of a co-receptor (CD4 or CD8) and its binding to MHC; mice expressing a faulty CD4 that cannot bind Class II fail to develop mature Th cells.
- Researchers are still trying to figure out what switches a cell’s genetic programming from Th to Tc. According to the instructional model, CD4 signals inhibit CD8 gene expression, leading to Th cell differentiation, while CD8 signals have the opposite effect, inhibiting CD4 expression and inducing Tc cell differentiation.
- The instructional model suggests that the cell might equally travel down either pathway, with the first sufficiently powerful signal determining its ultimate destination. Before positive selection can occur, the stochastic model predicts that the cell has already been committed to becoming a Tc or a Th.
- During positive selection, the cell will continue to follow its planned pathway only if it receives the correct signal through its co-receptor.
- The mammalian ortholog of Notch, a gene first discovered in Drosophila wing development and later found to be involved in a wide variety of developmental processes, may play a role.
- Notch may ordinarily act as an inhibitor of the Th development because its overexpression guides T cells into the Tc lineage. Recent research has also demonstrated that Notch expression is necessary for lymphoid progenitors to develop into T cells, with mice deficient in T cells when Notch is not expressed.
- Positive selection can also be affected by the peptides supplied by thymic epithelial cells. HLA-DM is an inhibitory molecule found in the MIIC vesicle, and it is blocked by HLA-DO, which is expressed by thymic epithelial cells (H-2O in mice). (Recall that DM eases the removal of CLIP and the binding of processed exogenous peptide to Class II.)
- Thymic epithelial cells display a wider variety of self peptides than any other APC and have higher levels of CLIP on their membrane Class II. Other data demonstrates that thymic epithelial cell proteases are distinct from APC proteases. The full significance of these results is not yet known.
- All of the Class II molecules in mice with a deficiency in the a chain of H-2M (the mouse counterpart of DM) exhibited CLIP. These animals displayed a decrease in the total number of CD4 T cells produced as well as a decrease in the number of CD4 T cells that were specifically reactive to CLIP, but not to other self peptides.
- They failed to show positive selection for cells transgenic for Class II-restricted TCR, perhaps because the transgenic TCR lacked CLIP peptide specificity. That the peptide has an effect on positive selection was shown by this finding.
- Self-specific T cells, which would have been negatively selected in typical mice, persisted in mice presenting just CLIP because of the robust response of H-2M-deficient T cells to self peptide presented on APC from syngeneic (having identical MHC alleles) mice.
- Most likely, positive selection for these self-specific T cells occurred because of their robust binding to Class II rather than to peptide, allowing for continued binding to syngeneic Class II containing distinct self peptides.
Negative Selection of T Cells
- Those T cells that make it through positive selection go on to encounter macrophages and dendritic cells, antigen-presenting cells (APC) originating from the bone marrow with high expression of MHC-self peptide complexes, at the cortico-medullary junction of the thymus.
- High-affinity self-peptide-MHC-binding T cells at this stage are eliminated via negative selection and apoptosis. Negative and positive forms of selection have been shown to exist using transgenic mice. There must be additional pathways for establishing peripheral tolerance, as not all self peptides are produced in the thymus.
- Negative selection relies heavily on bone marrow-derived APC, as shown by bone marrow chimaeras.
- Bone marrow from MHCaxb mice is transplanted into irradiated MHCa recipients, allowing the host MHCa thymic epithelial cells to be used as a positive selection target for the developing T cells while also exposing the developing T cells to donor MHCaxb macrophages and dendritic cells at the cortico-medullary junction.
- The chimaeras are tolerant not only of the host but also of the donor MHC + self peptide, as evidenced by their ability to accept skin grafts from MHCa and MHCb mice.
- Mice expressing an endogenous superantigen have been used to examine negative selection to self antigen. Strong signals are sent to mature Th cells by superantigens that bind to their TCR Vb region and MHC outside of the typical peptide-binding location, causing them to secrete cytokines and go into shock.
- These mice express self-peptides encoding a protein originally encoded by a gene from the mouse mammary tumour virus (MMTV), which has become integrated into the mouse genome. As T cells mature, those that contain the Vb region that binds the MMTV superantigen are programmed to die.
- T cells that have been engineered with Vb6, Vb8.1, or Vb9 segments are eradicated in mice expressing Mls-1a (one version of the superantigen). The number of these Vb segments is typical on mature T cells from animals that do not express Mls-1a.
- Single positive cells in the thymic medulla of Mls-1a+ animals do not express the Vb6, Vb8.1, or Vb9 segments, whereas double positive cells do. This difference suggests that negative selection occurs late in T cell development.
- In order for different types of T cells to survive and exit the thymus, the signals they get during positive and negative selection must be distinct. Positive selection has a lower avidity (more signal is needed to save the cells from death) and negative selection has a higher avidity (the same peptide-MHC complex supplies both signals), according to the differential avidity hypothesis (more signal is required to kill them).
- Increasing peptide presentation increased the number of T cells produced up to certain levels of peptide (positive selection), but increasing expression of the same peptide thereafter decreased the numbers of T cells produced, providing experimental support for the differential avidity model. This was demonstrated by experiments in which the avidity of signalling in thymus organ cultures was controlled by controlling the amount of peptide presented in TAP-deficient TCR-transgenic mice (negative selection).
- Positive and negative selection are hypothesised to send out qualitatively (and not just numerically) distinct signals, according to the differential signalling hypothesis. In order to test this idea, researchers use both agonist peptides, which activate T cells, and antagonist peptides, which send incomplete signals that prevent T cell activation by agonist peptides.
- The model suggests that antagonist peptides might transmit signals that result in positive selection, while only agonist peptides could transmit sufficiently strong signals that result in negative selection. This was found to be true for CD8 cells in thymus organ culture, but not for CD4 cells, which were unresponsive to antagonist peptides and hence unable to be positively selected.
- Direct cross-linking of the TCR and co-receptors resulted in varying degrees of positive selection of CD4 and CD8 cells. In the lack of peptide on MHC, cross-linking TCR and CD8 generates a partial signal and leads to the positive selection of CD8 T cells.
- By cross-linking TCR with CD4 or CD8, signals identical to normal activating signals were generated, allowing for the positive selection of CD4 T cells (Alberola-Ila et al., 1996).
- It might be assumed that expressing additional MHC genes will enhance pathogen antigen presentation because MHC molecules individually present several but not all peptides.
- Around 5% of T cells that are positively selected by self peptide on one MHC molecule are likely to be negatively selected by self peptide on another MHC molecule, offsetting this effect.
- In order to strike a balance between displaying more pathogen peptides and negatively selecting too many cells during development, we evolved with the number of MHC genes that we do. Having more MHC alleles in the population improves its ability to display more peptides.
- Limits exist, too, on the number of MHC proteins that can be expressed on the surface of a single cell. Keeping the amount of MHC proteins expressed by a given cell to a minimum ensures that each peptide-MHC complex is delivered with high enough avidity to the T cell.
- Similar to what we discovered with B cells, monoclonal T cell malignancies develop throughout distinct phases of T cell maturation and have unique membrane markers in predictable places. Additionally, certain rearrangements in the TCR gene help to positively identify them. Doubly positive T cells, surprisingly, do not appear to acquire malignant properties.
Differentiation of T Cells
- Lineage commitment, which is based on the T-cell receptor’s affinity for self-antigen, is the typical mechanism by which T cells undergo differentiation into specialised T cell subsets.
- During the double-positive thymocyte stage, cells decide whether to become CD8+ cytotoxic T cells or CD4+ helper T cells.
- For a gene to be silenced and a lineage-specific gene to be expressed, changes in genomic organisation and gene expression are required, both of which are a part of the lineage commitment process.
- Not everything about this process of differentiation has been figured out yet, but the most recent model that attempts to explain it points to the importance of a person’s preference for one of the two MHC classes.
Antigen Recognition By T Cells
- Major histocompatibility complex (MHC), or human leukocyte antigen (HLA) in humans, is an antigen presentation protein that T lymphocytes can only identify when they are presented on the surface as short peptides.
- Only professional antigen-presenting cells (APCs; B cells, dendritic cells (DCs), and macrophages) express MHC class II molecules, but MHC class I molecules are present on all nucleated cells. The choice of MHC to which a peptide will be loaded depends on the processing method used.
The HLA Locus
- A human’s HLA locus is located on the chromosome 6 short arm. The HLA-A, HLA-B, and HLAC loci make up the class I region. The D region, which is part of class II, is further broken down into the HLA-DP, HLA-DQ, and HLA-DR subregions.
- Class III proteins, which have no structural homology to either class I or class II molecules, are encoded by a region between the class I and class II loci.
- Complement proteins, tumour necrosis factor, and lymphotoxin are all examples of class III compounds.
- T cell recognition of foreign antigen and “self”/”non-self” discrimination rely heavily on the highly polymorphic class I and class II MHC components.
- In the event of a transplant, any MHC class I or class II molecules not already present in the recipient are recognised as foreign antigens and attacked accordingly.
- There is substantial allotypic polymorphism present in all MHC molecules; that is, there are differences in the sequences of some parts of the molecules from one individual to the next.
- Having the same allotype at all genes encoding MHC molecules is an extremely rare occurrence between two unrelated persons.
- All nucleated cells codominantly express the three MHC class I molecules, which differ from one another in amino acid sequence but are otherwise highly conserved.
- To have “codominant expression,” both copies of the genes producing these proteins must be active.
- Class II MHC molecules are unique in that their expression features a complex blend of homologous and heterologous αβ dimers, which together represent proteins from both parents. Subunit genes (both α and β ) are highly polymorphic on a species level.
- In contrast to the functional equivalence shared by homologous dimers, heterologous dimers are specific to the F1 genotype and are not shared with the parental class II molecules.
MHC Class I
- Class I MHC molecules recognise and bind peptides from cytosol-processed antigens, such as viral proteins synthesised by the host cell. The proteasome is a structure that breaks down proteins in the body spontaneously.
- The TAP (transporters associated with antigen processing) protein is responsible for the degradation and transport of antigens to the endoplasmic reticulum (ER), where the peptides are further processed and loaded onto the MHC class I.
- Binding of the peptide to MHC class I is followed by stabilisation of the complex by a β2-macroglobulin molecule and subsequent export to the cell membrane.
- CD8 T cells (cytotoxic T cells) specific for the attached peptide can now identify the full surface molecule.
MHC Class II
- Exogenous peptides from organelle-processed antigens are bound by MHC class II molecules.
- After engulfing an extracellular antigen by phagocytosis or endocytosis, APCs wrap it in a vesicle within the cell.
- In order to break down the antigen into smaller peptide fragments, the APCs get acidified upon activation, activating proteases in the process.
- Peptide-containing vesicles are joined with MHC class II protein-containing vesicles.
- Peptide specific CD4 T cells (helper T cells) can recognise it once it has fused with MHC class II molecules and been transported to the cell membrane surface.
Diseases Involving T Cells
Diseases that target T cells, a crucial part of the immune system, can have devastating effects very fast. T cell lymphoma and T cell mediated rejection are two further examples of such disorders that might have fatal consequences. As of right now, there is no cure for these conditions. Recent successes in stem cell study and other medicines, however, have opened up promising new doors.
Human Immunodeficiency Virus (HIV)
- HIV is a retrovirus that infects the immunological and nervous systems and has a spherical shape with a liquid envelope.
- The CD4 molecule (together with other receptors, such as CCR5 and CXCR4) on macrophages and CD4+ T cells is used as a portal for cell entrance.
- By binding to these receptors, HIV is able to fuse with the cell membrane and then inject its genome into the cytoplasm.
- An intracellular kinase gene called nef can be found in the genome. This may lead to the activation of afflicted T cells, viral replication, and increased infectiousness. It also causes a decrease in CD4+ and MHC molecules within the infected cells.
- Once the genome enters the cell, it undergoes reverse transcription to produce complementary DNA (cDNA). This cDNA is efficiently integrated into the genome of proliferating T cells, where it can remain dormant for months to years.
- Transcription of the proviral DNA can also result in the production of viral particles on the membrane of an infected cell, which can trigger the cell’s programmed death response.
- Memory In the early stages of HIV infection, when substantial cell death rates are present, the vast reservoir of lymphocytes is quickly depleted because CD4+ T cells are the first to be infected. At this stage, the virus has already spread throughout the body and triggered an immunological reaction.
- Through this mechanism, dendritic cells are enlisted, which then consume the infected T cells. Following antigen processing, dendritic cells transmit the modified antigen to functional CD4+ T cells. The viral infection then spreads swiftly throughout the body.
- Helper T cells, macrophages, and dendritic cells are then infected. Additional helper T cells then go on the offensive against the infected T cells, activating the immune system in two ways: humoral and cell-mediated.
- When T cells are depleted, a vicious loop is created. While the immune response isn’t yet at full strength, it can nevertheless fend off most new pathogens in this early stage.
- However, HIV relentlessly replicates and kills off the immune cells it infects in the subsequent phase. During clinical latency, the number of CD4+ T cells in the bloodstream gradually decreases.
- Eventually, there won’t be enough CD4+ cells to go around since they’ll be dying off quicker than they can multiply. Reduced CD4+ T-cell counts lead to the onset of acquired immunodeficiency syndrome (AIDS).
- Because of the compromised immune system, the body is more vulnerable to future infections.
- Therefore, HIV/AIDS is not fatal on its own. Patients with HIV/AIDS, however, do not mount a sufficient immune response to fend off illness.
- HIV has no definitive treatment available at this time. In contrast, the most effective treatments focus on avoiding the disease altogether or at least delaying its progression.
- Antiretroviral medication has been relatively effective in prolonging the health of HIV patients. Replacement of the lost white blood cells with HIV-resistant variants may, however, be the key to a complete cure, as suggested by new stem cell research.
T Cell Lymphoma
- T cell lymphoma is a kind of cancer in which T cells are targeted. It is initially produced by the infection of the human T cell leukaemia virus type 1 (HTLV-1), a type of retrovirus.
- It can develop in transverse myelitis, which is a disorder that leads in demyelination of the central nervous system.
- Typically, people presenting with T cell lymphoma have skin lesions, lymphadenopathy, hepatosplenomegaly, hypercalcemia, and different malignancies in the blood. The cells infected also exhibit large amounts of CD25.
- As an exceedingly aggressive tumour, patients typically last 8 months past diagnosis. Motivated to overcome this bad prognosis, various investigations have been done to develop effective treatments, including monoclonal antibodies, histone deacetylase inhibitors, anti-metabolites, and more immunomodulary medicines.
T Cell Mediated Rejection
- Transplanted organs can be rejected in the new body due to cell- mediated rejection and/or antibody- mediated rejection.
- This is usually when the host’s T cells do not identify the new organ’s cells as its own, resulting in immune system activation.
- Cytotoxic T cells damage the new organ’s cells, which can lead to parenchymal and endothelial cell death. CD4+ T cells stimulate inflammation, allowing lymphocytes and macrophages to fill the new organ.
- Additionally, microphages can target the cell and blood arteries, leading to reduced oxygen delivery in the organ.
- In order to safeguard the new organ, transplant recipients have to take immunosuppressive medicines to prevent their immune systems from activating.
- Typically, patients take these medicines for as long as they get the transplant. However, recent studies may discover that mingling the white blood cells from the suitable organ donor and the patient minimises organ reject.
- In this study, several of the patients were able to quit immunosuppressive drug treatments without organ rejection for at least two years.
Function of T cells in Immune system
- T cells make up the majority of the adaptive immune system. It participates in the direct destruction of infected host cells, the creation of cytokines, the activation of immune cells, and the modulation of immunological responses.
- T cells are responsible for the maintenance and establishment of immunological responses, memory, and homeostasis.
- They express receptors to recognise antigens from pathogens and the environment, to maintain self-tolerance, and to store immunological memory.
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