T cells , or Lymphocytes , are a type of lymphocytes (white blood cell subtypes) that play a central role in cellular immunity. T cells can be distinguished from other lymphocytes, such as B cells and natural killer cells, in the presence of T-cell receptors on the cell surface. They are called T cells because they are mature in the thymus of thymocytes (although some are also mature in the tonsils). Some subset of T cells each have different functions. The majority of human T cells reorganize their alpha and beta chains on cell receptors and are called T alpha beta cells (T cells) and are part of the adaptive immune system. Specific gamma delta T cells, (a small minority of human T cells, more common in ruminant animals), have limited invariant T cell receptors, which can effectively present antigens to other T cells and are considered part of the innate immune system.
Video T cell
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Effector
Effector cells are a superset of all different types of T cells that actively respond immediately to stimuli, such as co-stimulation. These include helper, killer, regulation, and potentially other T cell types. Memory cells are their longer-lived counterparts alive to target future infections if needed.
Helper
T helper cells (T H cells) assist other white blood cells in immunological processes, including B cell maturation into plasma cells and B memory cells, and activation of cytotoxic T cells and macrophages. These cells are also known as CD4 T cells because they express the CD4 glycoprotein on its surface. Helper T cells become active when they are presented with peptide antigens by class II MHC molecules, expressed on the antigen-presenting cell surface (APCs). Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the active immune response. These cells can differentiate into one of several subtypes, including T H 1, T H 2, T H 3, T H 17, T H 9, or T FH , which secretes various cytokines to facilitate different types of immune responses. Signaling from APC directs T cells to a specific subtype.
Cytotoxic (Killer)
Cytotoxic T cells (T C cells, CTL, T-killer cells, killer T cells) destroy cells infected with viruses and tumor cells, and are also involved in transplant rejection. These cells are also known as cell CD8 T because these cells express the CD8 glycoprotein on its surface. These cells recognize their targets by binding to antigens associated with the class I MHC molecule, which is on the surface of all nucleated cells. Through IL-10, adenosine, and other molecules secreted by T regulator cells, CD8 cells can be disabled to anergic state, which prevents autoimmune disease.
Memory
The antigen-naÃÆ'¯ve T cells develop and differentiate into memory T cells and effector after they find their cognitive antigen in the context of MHC molecules on the surface of antigen cells that present professionals (eg dendritic cells). Appropriate co-stimulation should be present at the antigen meeting for this process to occur. Historically, memory T cells were thought to belong to either the effector or the central memory subtype, each with their own distinguishing cell surface markers (see below). Furthermore, many new populations of memory T cells were found including network-population T (Trm) cell memory, TSCM memory stem cells, and T virtual memory cells. The single unifying theme for all memory T-cell subtypes is that they are long-lived and can rapidly expand to a large number of effector T cells after re-exposure to their cognitive antigens. By this mechanism they provide a "memory" immune system against previously encountered pathogens. Memory T cells can be either CD4 or CD8 and usually express CD45RO.
T cell memory subtype:
- The central memory T cells (T CM ) express CD45RO, C-C type 7 (CCR7) and L-selectin (CD62L) chemokrin receptors. Central memory T cells also have medium to high CD44 expression. This memory subpopulation is usually found in lymph nodes and in peripheral circulation. (Note-expression CD44 is commonly used to distinguish murine naive from memory T cells).
- The T cell cell memory (T EM cell and T EMRA/cell sub) cells express CD45RO but do not have CCR7 and L-selectin expressions. They also have medium to high CD44 expression. These memory T cells are less lymph node receptors and thus are found in peripheral and tissue circulation. T EMRA stands for distinctively differentiated effector-memory cells expressing CD45RA, which is a marker normally found in naive T cells.
- Tissue resident memory T cells (T RM ) occupy tissue (skin, lungs, etc.) without recirculation. One cell surface marker that has been associated with T RM is integrin? E? 7.
- The virtual memory of T cells is different from other memory subsets because it does not come from strong clonal expansion events. Thus, although this population as a whole is abundant in the peripheral circulation, individual virtual memory, T cell clones are at relatively low frequencies. One theory is that homeostatic proliferation raises this T-cell population. Although CD8 virtual T cell memory is the first to be described, it is now known that the CD4 virtual memory cells also exist.
Rule (suppressor)
Regulatory T cells (suppressor T cells) are essential for the maintenance of immunological tolerance. Its main role is to shut down T cell-mediated immunity toward the end of an immune response and suppress autoreactive T cells that pass the negative selection process in the thymus. The suppressor T cells together with Helper T cells may be collectively called Regulatory T cells because of their regulatory function.
Two major classes of CD4 T reg cells have been described - FOXP3 T reg cells and FOXP3 < sup> T reg cells.
Regulatory T cells can develop well during normal development in the thymus, and then become known as Tym thymus cells, or can be induced peripherally and are called peripheral derived Treg cells. These two subgroups were previously called "natural", and "adaptive" or "induced", respectively. Both subsets require the expression of the FOXP3 transcription factor that can be used to identify cells. Gene mutation FOXP3 can prevent the development of regulatory T cells, causing fatal autoimmune IPEX disease.
Some other T-cell types have pressing activity, but do not express FOXP3. These include Tr1 cells and Th3 cells, which are thought to originate during the immune response and act by producing suppressive molecules. The Tr1 cells are associated with IL-10, and Th3 cells are associated with TGF-beta. Recently, Treg17 cells have been added to this list.
Natural killer T cells
Natural killer T cells (HCV cells - not to be confused with the natural killer cells of the innate immune system) bridge the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigens presented by major histocompatibility complex molecules (MHCs), NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions that are thought to originate from T h and T c cells (ie, cytokine production and release of cytolytic/cellular killer molecules). They are also able to recognize and eliminate some tumor cells and cells infected with the herpes virus.
Mucosal related invariant
The MAIT cell displays native, quality like an effector. In humans, MAIT cells are found in blood, liver, lung, and mucosa, defending against microbial activity and infection. Proteins such as MHC-class I, MR1, are responsible for presenting vitamin B metabolites produced by bacteria for MAIT cells. After the presentation of foreign antigens by MR1, MAIT cells secrete pro-inflammatory cytokines and are able to lyse bacterial infected cells. MAIT cells can also be activated by MR1-independent signaling. In addition to having this innate function, this T-cell subset supports an adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence has not been published.
Gamma delta T cells
Gamma delta cells (T cells) are a small subset of T cells that have different T-cell receptors (TCRs) on their surfaces. The majority of T cells have a TCR consisting of two chains called glycoproteins? - and? - TCR. However, in ?? T cells, TCR consists of one chain and one chain. This group of T cells is much less common in humans and mice (about 2% of total T cells); and most are found in the intestinal mucosa, in lymphocyte populations known as intraepithelial lymphocytes. In rabbits, sheep, and chickens, the amount of ?? T cells can be as high as 60% of total T cells. The antigenic molecule that activates ?? T cells are still not widely known. However, ?? T cells are not limited to MHC and seem to be able to recognize all proteins rather than requiring peptides to be presented by MHC molecules to APC. Some murine ?? T cells recognize IBC IB class molecules, though. Man V? 9/V? 2 T cells, which is the main ?? The population of T cells in peripheral blood, is unique in that they specifically and rapidly respond to a set of phosphorylated phosphorylated isoprenoid precursors, collectively called phosphoantigens, produced by virtually all living cells. The most common phosphantogens of animal and human cells (including cancer cells) are isopentenyl pyrophosphate (IPP) and dimethylene pyrophosphate isomer (DMPP). Many microbes produce highly active hydroxy-DMAPP compounds (HMB-PP) and corresponding mononucleotide conjugates, in addition to IPP and DMAPP. Plant cells produce both types of phosphoantigens. Drugs that activate human V cells? 9/V? 2 T consists of phosphoantigens and synthetic aminobisphosphonate, which increase endogenous IPP/DMAPP regulation.
Maps T cell
Development
All T cells come from hematopoietic stem cells in the bone marrow. Haematopoietic progenitors (lymphoid progenitor cells) from hematopoietic stem cells fill the thymus and expand by cell division to produce large populations of immature thymocytes. Early thymocytes do not express CD4 or CD8, and are therefore classified as double-negative cells (CD4 - CD8 - ). As they progress through their development, they become positively double thymocytes (CD4 CD8 ), and finally mature for one-positive (CD4 CD8 - or CD4 - CD8 ) thymocytes which are then released from the thymus to the peripheral tissue. There is some evidence of double positive T-cells on the periphery, although their prevalence and function are uncertain. In the laboratory, T-cells can be converted into functional neurons within three weeks.
Approximately 98% of thymocytes die during the developmental process in the thymus by failing either positive selection or negative selection, while the other 2% survive and leave the thymus to become adult immunocompetent T cells. Increasing evidence suggests microRNAs, which are small noncoding regulator RNAs, can have an impact on clonal selection during thymic development. For example, miR-181a was found to play a role in the positive selection of T lymphocytes.
The thymus contributes less cells as one gets older. When the thymus shrinks by about 3% per year throughout middle age, a corresponding decrease in thymus production of naà ± t T cells occurs, leaving a peripheral T-cell expansion to play a greater role in protecting older subjects.
Options beta
Common lymphoid precursor cells that migrate to the thymus become known as T-cell precursors (or thymocytes) and do not express T cell receptors. Broadly speaking, the double negative stage (DN) is focused on producing functional chains while the positive double stage (DP) is focused on the production of chain-functional, which ultimately produces functional ?? T cell receptor. As the thymocyte progresses through the four stages of DN (DN1, DN2, DN3, and DN4), T cells express an irregular "chain" but rearrange the chain-locus. If reorder? - chain successfully paired with inverted chains, a signal is generated that stops the rearrangement of the chain (and silences alternate alleles) and produces cell proliferation. Although these signals require pre-TCR on the cell surface, this signal is independent of the ligand bond to pre-TCR. These thymocytes will then express CD4 and CD8 and progress to the double positive stage (DP) where chain-selection occurs. If the rearranged chain does not lead to any signaling (eg, as a result of the inability to pair with the invariant chain), the cell may die from negligence (lack of signal).
Positive choice
Positive Selection "opts for" T cells capable of interacting with MHC. Positive selection involves the production of signals by double-positive precursors expressing Class I or II MHC receptors. The signals generated by these thymocytes result in RAG gene repression, long-term survival and migration to the medulla, and differentiation into mature T cells. A positive selection process takes several days.
Double-positive thymocytes (CD4 /CD8 ) move deep into the thymic cortic, where they are presented with self-antigen. These antigens are expressed by cortical thymic epithelial cells in MHC molecules on the surface of cortical epithelial cells. Only thymocytes interacting with MHC-I or MHC-II properly (ie, not too strong or too weak) will receive a vital "survival signal". All that can not (ie, if they do not interact strong enough, or if they bind too strongly) will die by "death by negligence" (no sign of survival). This process ensures that selected T cells will have MHC affinities that can function in the body (ie cells must be able to interact with MHC and peptide complexes to influence the immune response). Most of all thymocytes will die during this process.
The fate of a thymocyte is determined during a positive selection. Double positive cells (CD4 /CD8 ) that interact well with class II MHC molecules will eventually become CD4 cells, while interacting thymocytes well with mature class I MHC molecules into CD8 cells. T cells become CD4 cells by expression that regulates its CD8 cell surface receptor. If the cell does not lose its signal, it will continue to decrease the CD8 setting and become CD4 , a single positive cell. But, if there is a signal interruption, the cell stops lowering the CD8 regulation and switches down to regulate the CD4 molecule, in contrast, eventually becoming CD8 , a single positive cell.
This process does not eliminate thymocytes that can cause autoimmunity. The potential autoimmune cells are removed by a negative selection process, which occurs in the medulla thymus (discussed below).
Negative choice
Negative selection removes thymocytes that are able to bind with strong "self" MHC peptides. Thymocytes that survive positive selection migrate toward the boundary of the cortex and the medulla in the thymus. While in the medulla, they were again presented with self antigen presented at the MHC complex of medullary thymic medullary cells (mTECs). mTEC should be AIRE to express self antigen from all body tissues on class I MHC peptides. Some mTECs are phagocytosis by thymic dendritic cells; this allows for the presentation of self-antigen in class II MHC molecules (selectable cells) should interact with class II MHC molecules, so APC, which has MHC class II, should be present for CD4 Negative Selection of T-cells). Thymocytes that interact too strongly with self-antigens receive apoptotic signals leading to cell death. However, some of these cells are selected to be Treg cells. The remaining cells come out of the thymus as immature naeg T cells (also known as new thymus emigrants). This process is an essential component of central tolerance and serves to prevent the formation of self-reactive T cells capable of inducing autoimmune disease in the host.
In short, the selection is the first checkpoint, where T cells capable of forming a pre-TCR function with invariant alpha chains and functional beta chains are permitted to continue development in the thymus. Furthermore, positive selection checks that T cells have successfully rearranged their TCR? locus and are able to recognize the peptide-MHC complex with appropriate affinity. Negative selection in the medulla then eliminates T cells that bind too strongly to self-antigens expressed on MHC molecules. This selection process allows self-tolerance by the immune system. Typical T cells that leave the thymus (via the corticomedullarly intersection) are self-restricted, self-tolerant, and singlely positive.
Activation
Activation of CD4 T cells occur through the simultaneous involvement of T cell receptors and co-stimulatory molecules (such as CD28, or ICOS) in T cells by the major pituitary histocompatibility complex (MHCII) and co-stimulatory molecules in APC. Both are required for the production of an effective immune response; in the absence of co-stimulation, the T cell receptor itself produces anergy. The downstream signaling pathway of the co-stimulating molecule usually involves a PI3K pathway that produces PIP3 in the plasma membrane and recruits a PH domain containing a signaling molecule such as PDK1 that is essential for CCP activation, and finally IL-2 production. Optimal CD8 T-cell response depends on CD4 CD4 signaling. The CD4 cell is useful in early activation of T cell antigenic na'¯ve CD8, and retains CD8 memory cells of T after acute infection. Therefore, CD4 T-cell activation T may be beneficial for CD8 T cell action T.
The first signal is given by the binding of the T cell receptor to its cognitive peptide presented at MHCII on APC. MHCII is limited to so-called professional antigen-presenting cells, such as dendritic cells, B cells, and macrophages, to name a few. Peptides presented to CD8 T cells by class I MHC molecules have a length of 8-13 amino acids; peptides presented to CD4 cells by second class MHC molecules are longer, usually 12-25 amino acids in length, because the binding ends of the class II MHC molecule are open.
The second signal comes from co-stimulation, in which the surface receptor on APC is induced by a small amount of stimulation, usually a pathogenic product, but sometimes damages cell products, such as necrotic-body or heat-shock proteins. The only co-stimulating receptor expressed constitutively by naï¯ve T cells is CD28, so the co-stimulation for these cells comes from the CD80 and CD86 proteins, which together form the B7 protein, (B7.1 and B7.2, respectively). on APC. Other receptors are expressed after T cell activation, such as OX40 and ICOS, but this is highly dependent on CD28 for their expression. The second signal licenses T cells to respond to antigens. Without it, T cells become anergic, and it becomes more difficult to activate in the future. This mechanism prevents inappropriate responses to self, since self-peptides are not usually presented with appropriate joint stimulation. Once the T cells have been activated appropriately (ie having received signal one and signal two) it alters the cell surface expression of the various proteins. T cell activation markers include CD69, CD71 and CD25 (also markers for Treg cells), and HLA-DR (a marker of human T cell activation). Expressions of CTLA-4 are also regulated on activated T cells, which in turn compete with CD28 to bind protein B7. This is a checkpoint mechanism to prevent excessive activation of T cells. Activated T cells also alter their cell surface glycosylation profiles.
T cell receptors exist as multiple protein complexes. The actual T cell receptor consists of two separate peptide chains, which are generated from the independent alpha and beta receptor gene ( TCR and TCR? Gene) genes. Another protein in the complex is a CD3: CD3 protein ?? and CD3 ?? heterodimer and, most importantly, CD3? homodimer, which has a total of six motives ITAM. ITAM Motive on CD3? can be phosphorylated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 may also phosphorylate tyrosine in many other molecules, not least CD28, LAT and SLP-76, which allow complex aggregation of signaling around this protein.
Phosphorylated LAT recruits SLP-76 to the membrane, where it can carry PLC- ?, VAV1, Itk and potentially PI3K. PLC-? cut PI (4.5) P2 on the inner membrane of the membrane to create active intermediate diacylglycerol (DAG), inositol-1,4,5-trisphosphate (IP3); PI3K also acts on PIP2, phosphorylating to produce phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some CCPs. The most important thing in T cells is CCP ?, it is important to activate transcription factor NF-? B and AP-1. IP3 released from membrane by PLC-? and diffuse rapidly to activate calcium channel receptors in ER, which induces calcium release into the cytosol. Low calcium in the endoplasmic reticulum causes STIM1 to cluster on the ER membrane and lead to the activation of CRAC membrane cell membranes that allow additional calcium to flow into the cytosol from the extracellular space. This cytosolic calcium aggregates binds calmodulin, which can then activate calcineurin. Calcineurin, in turn, activates NFAT, which then translocates to the nucleus. NFAT is a transcription factor that activates transcription of a set of pleiotropic genes, most importantly, IL-2, a cytokine that promotes long-term proliferation of activated T cells.
PLC? also can start the path of NF-? B. DAG activates the CCP ?, which then phosphorylates CARMA1, causing it to unfold and function as a scaffold. Cytosolic domains bind domain BCL10 adapter through KARD domain (Caspase activation and recruitment domains); which then binds TRAF6, which is ubiquitous in K63. This form of ubiquitination does not cause the degradation of target proteins. Instead, serves to recruit NEMO, IKK? and - ?, and TAB1-2/TAK1. NO 1 phosphorylates IKK-, which then phosphorylates I? B allows for ubiquitination K48: leads to proteasomal degradation. Rail A and p50 can then enter the nucleus and bind the NF-B response element. This coupled with NFAT signaling allows for full activation of the IL-2 gene.
While in many cases activation depends on the recognition of TCR antigen, an alternative pathway for activation has been described. For example, cytotoxic T cells have been shown to be active when targeted by other CD8 T cells leading to the latter tolerance.
In spring 2014, the T-Cell Activation in Space (TCAS) experiment was launched into the International Space Station at SpaceX CRS-3 mission to study how "deficiencies in the human immune system are affected by microgravity environments".
T cell activation is modulated by reactive oxygen species.
Discrimination antigen
The unique feature of T cells is their ability to differentiate between healthy and abnormal cells (eg infected cells or cancer) in the body. Healthy cells usually express large numbers of self-derived pMHCs on the surface of their cells and although T cell antigen receptors may interact with at least some of the pMHCs themselves, T cells generally ignore these healthy cells. However, when these same cells contain the number of pathogenic pMHCs derived from pMHC cells, T cells can become active and initiate an immune response. The ability of T cells to ignore healthy cells but responds when these same cells contain pathogenic pMHC (or cancer) known as antigen discrimination. The molecular mechanisms underlying this process are controversial.
Clinical interests
Disadvantages
Causes of T cell deficiency include T-cell lymphocytopenia and/or defects in individual T-cell functions. Insufficient T cell function may occur due to hereditary conditions such as severe combined immunodeficiency (SCID), Omenn syndrome, and cartilage hypoplasia. Causes of partial insufficiency of T-cell function include acquired immune deficiency syndrome (AIDS), and hereditary conditions such as DiGeorge syndrome (DGS), chromosomal damage syndrome (CBSs), and B-cell and T-cell combined disorders such as ataxia-telangiectasia. (AT) and Wiskott-Aldrich syndrome (WAS).
The main pathogens concerned with T cell deficiency are intracellular pathogens, including Herpes simplex virus Mycobacterium and Listeria . Also, fungal infections are also more common and severe in T cell deficiency.
Cancer
T cell cancer is called T cell lymphoma, and accounts for perhaps one in ten cases of non-Hodgkin's lymphoma. The main forms of T cell lymphoma are:
- Extranodal T cell lymphoma
- Cutaneous T cell lymphoma: Zary's syndrome and mycosis Fungoides
- Anaplastic large cell lymphoma
- Anemonimmoblastic T cell lymphoma
Fatigue
T cell fatigue is the loss of a progressive T cell function. May occur during sepsis and after other acute or chronic infections.
T cell fatigue is mediated by several inhibitory receptors including programmed cell death protein 1 (PD1), TIM3, and 3 lymphocyte gene activation genes (LAG3).
CD8 T cell exhaustion occurs in some tumors, and may be partially reversed by blocking inhibitory receptors (eg PD1).
T cell fatigue is associated with epigenetic changes in T cells.
(See also functional disregulation of Immunosenescence # T as biomarkers for immunosenescence).
Research
Genetic engineering
In 2015, a team of researchers led by Dr. Alexander Marson at the University of California, San Francisco successfully edited the human T cell genome using the Cason ribonucleotoprotein delivery method. These advances have potential for application in treating "cancer-based immunotherapy and cell-based therapy for HIV, primary immune deficiency, and autoimmune disease".
See also
- Homing specific gri
- Immunoblast
- Immunosenescence
- Streptamer
References
External links
- Immunobiology, 5th Edition
- niaid.nih.gov - Immune System
- T Group - Cardiff University
- (Successful!) Treatment of Metastatic Melanoma with Autologous CD4 T cells against NY-ESO-1.
- Davies AJ (1993). "T-cell story". Immunology Today . 14 (3): 137-139. doi: 10.1016/0167-5699 (93) 90216-8. PMID 8466629.
Source of the article : Wikipedia
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