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124-408: Microtubule-organizing centers function as the site where microtubule formation begins, as well as a location where free-ends of microtubules attract to. Within the cells, microtubule-organizing centers can take on many different forms. An array of microtubules can arrange themselves in a pinwheel structure to form the basal bodies, which can lead to the formation of microtubule arrays in the cytoplasm or

248-435: A CD4 , both CD8 and CD4 cells are now single positive cells. This process does not filter for thymocytes that may cause autoimmunity . The potentially autoimmune cells are removed by the following process of negative selection, which occurs in the thymic medulla. Negative selection removes thymocytes that are capable of strongly binding with "self" MHC molecules. Thymocytes that survive positive selection migrate towards

372-518: A DN4 cell (CD25 CD44 ). These cells then undergo a round of proliferation, and begin to re-arrange the TCRα locus during the double-positive stage. The process of positive selection takes 3 to 4 days and occurs in the thymic cortex. Double-positive thymocytes (CD4 /CD8 ) migrate deep into the thymic cortex , where they are presented with self- antigens . These self-antigens are expressed by thymic cortical epithelial cells on MHC molecules, which reside on

496-467: A T cell has been appropriately activated (i.e. has received signal one and signal two) it alters its cell surface expression of a variety of proteins. Markers of T cell activation include CD69, CD71 and CD25 (also a marker for Treg cells), and HLA-DR (a marker of human T cell activation). CTLA-4 expression is also up-regulated on activated T cells, which in turn outcompetes CD28 for binding to the B7 proteins. This

620-450: A co-stimulatory molecule (like CD28 , or ICOS ) on the T cell by the major histocompatibility complex (MHCII) peptide and co-stimulatory molecules on the APC . Both are required for production of an effective immune response; in the absence of co-stimulation , T cell receptor signalling alone results in anergy . The signalling pathways downstream from co-stimulatory molecules usually engages

744-447: A complete set of chromatids, and for this to happen each sister chromatid has to anchor (through the corresponding kinetochore) to MTs generated in opposed poles of the mitotic spindle. This configuration is termed amphitelic or bi-orientation . However, during the anchoring process some incorrect configurations may also appear: Both the monotelic and the syntelic configurations fail to generate centromeric tension and are detected by

868-458: A complex method (termed "multiclassifier combinatorial proteomics" or MCCP) to analyze the proteomic composition of vertebrate chromosomes, including kinetochores. Although this study does not include a biochemical enrichment for kinetochores, obtained data include all the centromeric subcomplexes, with peptides from all 125 known centromeric proteins. According to this study, there are still about one hundred unknown kinetochore proteins, doubling

992-512: A delay in cell cycle progression: the cell is arrested, allowing time for repair mechanisms to solve the detected problem. After some time, if the problem has not been solved, the cell will be targeted for apoptosis (programmed cell death), a safety mechanism to avoid the generation of aneuploidy , a situation which generally has dramatic consequences for the organism. Whereas structural centromeric proteins (such as CENP-B ), remain stably localized throughout mitosis (including during telophase ),

1116-462: A freshman in 1932. Monocentric organisms, including vertebrates, fungi, and most plants, have a single centromeric region on each chromosome which assembles a single, localized kinetochore. Holocentric organisms , such as nematodes and some plants, assemble a kinetochore along the entire length of a chromosome. Kinetochores start, control, and supervise the striking movements of chromosomes during cell division. During mitosis, which occurs after

1240-440: A functional alpha chain. Once a working TCR has been produced, the cells then must test if their TCR will identify threats correctly, and to do this it is required to recognize the body’s major histocompatibility complex (MHC) in a process known as positive selection. The thymocyte must also ensure that it does not react adversely to "self" antigens , called negative selection. If both positive and negative selection are successful,

1364-401: A kinetochore become stabilized, whereas those microtubules remaining free are rapidly depolymerized. As chromosomes have two kinetochores associated back-to-back (one on each sister chromatid), when one of them becomes attached to the microtubules generated by one of the cellular poles, the kinetochore on the sister chromatid becomes exposed to the opposed pole; for this reason, most of the times

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1488-472: A laser beam, they rapidly depolymerize. When it was clear that neither dynein nor CENP-E is essential for kMTs formation, other molecules should be responsible for kMTs stabilization. Pioneer genetic work in yeast revealed the relevance of the Ndc80 complex in kMTs anchoring. In Saccharomyces cerevisiae , the Ndc80 complex has four components: Ndc80p , Nuf2p , Spc24p and Spc25p . Mutants lacking any of

1612-453: A microtubule, allowing vesicles to be directed to or from the endoplasmic reticulum and Golgi apparatus. Particularly for the Golgi apparatus, structures associated with the apparatus travel towards the minus end of a microtubule and aid in the overall structure and site of the Golgi in the cell. Movements of the microtubules are based on the actions of the centrosome. Each daughter cell after

1736-526: A molecular pathway which is additive to cohesin pathway, and it is mostly unknown. Most chromosome movements in relation to spindle poles are associated to lengthening and shortening of kMTs. One of the features of kinetochores is their capacity to modify the state of their associated kMTs (around 20) from a depolymerization state at their (+) end to polymerization state. This allows the kinetochores from cells at prometaphase to show "directional instability", changing between persistent phases of movement towards

1860-445: A role in T cell exhaustion are regulatory cells. Treg cells can be a source of IL-10 and TGF-β and therefore they can play a role in T cell exhaustion. Furthermore, T cell exhaustion is reverted after depletion of Treg cells and blockade of PD1. T cell exhaustion can also occur during sepsis as a result of cytokine storm. Later after the initial septic encounter anti-inflammatory cytokines and pro-apoptotic proteins take over to protect

1984-547: A round of division and downregulate c-kit and are termed double-negative one (DN1) cells. To become T cells, the thymocytes must undergo multiple DN stages as well as positive selection and negative selection. Double negative thymocytes can be identified by the surface expression of CD2 , CD5 and CD7 . Still during the double negative stages, CD34 expression stops and CD1 is expressed. Expression of both CD4 and CD8 makes them double positive , and matures into either CD4 or CD8 cells. A critical step in T cell maturation

2108-569: A series of subsets based on their function. CD4 and CD8 T cells are selected in the thymus, but undergo further differentiation in the periphery to specialized cells which have different functions. T cell subsets were initially defined by function, but also have associated gene or protein expression patterns. T helper cells (T H cells) assist other lymphocytes, including the maturation of B cells into plasma cells and memory B cells , and activation of cytotoxic T cells and macrophages . These cells are also known as CD4 T cells as they express

2232-415: A specialized histone H3 variant (called CENP-A or CenH3) which helps the kinetochore associate with DNA. Other proteins in the kinetochore adhere it to the microtubules (MTs) of the mitotic spindle . There are also motor proteins , including both dynein and kinesin , which generate forces that move chromosomes during mitosis. Other proteins, such as Mad2 , monitor the microtubule attachment as well as

2356-765: Is CD28, so co-stimulation for these cells comes from the CD80 and CD86 proteins, which together constitute the B7 protein, (B7.1 and B7.2, respectively) on the APC. Other receptors are expressed upon activation of the T cell, such as OX40 and ICOS, but these largely depend upon CD28 for their expression. The second signal licenses the T cell to respond to an antigen. Without it, the T cell becomes anergic , and it becomes more difficult for it to activate in future. This mechanism prevents inappropriate responses to self, as self-peptides will not usually be presented with suitable co-stimulation. Once

2480-529: Is PKC-θ, critical for activating the transcription factors NF-κB and AP-1. IP3 is released from the membrane by PLC-γ and diffuses rapidly to activate calcium channel receptors on the ER , which induces the release of calcium into the cytosol. Low calcium in the endoplasmic reticulum causes STIM1 clustering on the ER membrane and leads to activation of cell membrane CRAC channels that allows additional calcium to flow into

2604-412: Is a checkpoint mechanism to prevent over activation of the T cell. Activated T cells also change their cell surface glycosylation profile. The T cell receptor exists as a complex of several proteins. The actual T cell receptor is composed of two separate peptide chains, which are produced from the independent T cell receptor alpha and beta ( TCRα and TCRβ ) genes. The other proteins in the complex are

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2728-452: Is a protein located at the centrosome that nucleates the microtubules by interacting with the tubulin monomer subunit in the microtubule at the minus end. Organization of the microtubules at the MTOC, or centrosome in this case, is determined by the polarity of the microtubules defined by y-tubulin. In epithelial cells, MTOCs also anchor and organize the microtubules that make up cilia. As with

2852-449: Is determined during positive selection. Double-positive cells (CD4 /CD8 ) that interact well with MHC class II molecules will eventually become CD4 "helper" cells, whereas thymocytes that interact well with MHC class I molecules mature into CD8 "killer" cells. A thymocyte becomes a CD4 cell by down-regulating expression of its CD8 cell surface receptors. If the cell does not lose its signal, it will continue downregulating CD8 and become

2976-587: Is followed by the loss of high proliferative capacity and cytotoxic potential, and eventually leads to their deletion. Exhausted T cells typically indicate higher levels of CD43 , CD69 and inhibitory receptors combined with lower expression of CD62L and CD127 . Exhaustion can develop during chronic infections, sepsis and cancer. Exhausted T cells preserve their functional exhaustion even after repeated antigen exposure. T cell exhaustion can be triggered by several factors like persistent antigen exposure and lack of CD4 T cell help. Antigen exposure also has effect on

3100-410: Is frequently overexpressed in several cancer types, and it is currently a target for the development of anticancer drugs. The spindle checkpoint, or SAC (for spindle assembly checkpoint ), also known as the mitotic checkpoint , is a cellular mechanism responsible for detection of: When just one chromosome (for any reason) remains lagging during congression, the spindle checkpoint machinery generates

3224-518: Is independent of CENP-I/MIS6 in human cells. In C. elegans and metazoa, the incorporation of many proteins in the outer kinetochore depends ultimately on CENP-A. Kinetochore proteins can be grouped according to their concentration at kinetochores during mitosis: some proteins remain bound throughout cell division, whereas some others change in concentration. Furthermore, they can be recycled in their binding site on kinetochores either slowly (they are rather stable) or rapidly (dynamic). A 2010 study used

3348-1002: Is known as antigen discrimination. The molecular mechanisms that underlie this process are controversial. Causes of T cell deficiency include lymphocytopenia of T cells and/or defects on function of individual T cells. Complete insufficiency of T cell function can result from hereditary conditions such as severe combined immunodeficiency (SCID), Omenn syndrome , and cartilage–hair hypoplasia . Causes of partial insufficiencies of T cell function include acquired immune deficiency syndrome (AIDS), and hereditary conditions such as DiGeorge syndrome (DGS), chromosomal breakage syndromes (CBSs), and B cell and T cell combined disorders such as ataxia-telangiectasia (AT) and Wiskott–Aldrich syndrome (WAS). The main pathogens of concern in T cell deficiencies are intracellular pathogens , including Herpes simplex virus , Mycobacterium and Listeria . Also, fungal infections are also more common and severe in T cell deficiencies. Cancer of T cells

3472-481: Is making a functional T cell receptor (TCR). Each mature T cell will ultimately contain a unique TCR that reacts to a random pattern, allowing the immune system to recognize many different types of pathogens . This process is essential in developing immunity to threats that the immune system has not encountered before, since due to random variation there will always be at least one TCR to match any new pathogen. A thymocyte can only become an active T cell when it survives

3596-586: Is much less common in humans and mice (about 2% of total T cells) and are found mostly in the gut mucosa , within a population of intraepithelial lymphocytes . In rabbits, sheep, and chickens, the number of γδ T cells can be as high as 60% of total T cells. The antigenic molecules that activate γδ T cells are still mostly unknown. However, γδ T cells are not MHC-restricted and seem to be able to recognize whole proteins rather than requiring peptides to be presented by MHC molecules on APCs . Some murine γδ T cells recognize MHC class IB molecules. Human γδ T cells that use

3720-448: Is released from kinetochores as they acquire kMTs and, in cultured mammalian cells, it is required for the spindle checkpoint inactivation, but not for chromosome congression in the spindle equator, kMTs acquisition or anaphase A during chromosome segregation. In higher plants or in yeast there is no evidence of dynein, but other kinesins towards the (-) end might compensate for the lack of dynein. Another motor protein implicated in

3844-422: Is surrounded by pericentriolar material (PCM) that is important for microtubule nucleation. Microtubules are anchored at the MTOC by their minus ends, while their plus ends continue to grow into the cell periphery. The polarity of the microtubules is important for cellular transport, as the motor proteins kinesin and dynein typically move preferentially in the "plus" and "minus" directions respectively, along

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3968-459: Is termed T-cell lymphoma , and accounts for perhaps one in ten cases of non-Hodgkin lymphoma . The main forms of T cell lymphoma are: T cell exhaustion is a poorly defined or ambiguous term. There are three approaches to its definition. "The first approach primarily defines as exhausted the cells that present the same cellular dysfunction (typically, the absence of an expected effector response). The second approach primarily defines as exhausted

4092-436: Is that they are long-lived and can quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen. By this mechanism they provide the immune system with "memory" against previously encountered pathogens. Memory T cells may be either CD4 or CD8 and usually express CD45RO . Memory T cell subtypes: Regulatory T cells are crucial for the maintenance of immunological tolerance . Their major role

4216-621: Is to shut down T cell–mediated immunity toward the end of an immune reaction and to suppress autoreactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4 T reg cells have been described—FOXP3 T reg cells and FOXP3 T reg cells. Regulatory T cells can develop either during normal development in the thymus, and are then known as thymic Treg cells, or can be induced peripherally and are called peripherally derived Treg cells. These two subsets were previously called "naturally occurring" and "adaptive" (or "induced"), respectively. Both subsets require

4340-412: The 9+2 axoneme . Other arrangements range from fungi spindle pole bodies to the eukaryotic chromosomal kinetochores (flat, laminated plaques). MTOCs can be freely dispersed throughout the cytoplasm or centrally localized as foci. The most notable MTOCs are the centrosome at interphase and the mitotic spindle poles. Centrioles can act as markers for MTOCs in the cell. If they are freely distributed in

4464-549: The CD3 proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. The ITAM motifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70 . Lck and/or ZAP-70 can also phosphorylate the tyrosines on many other molecules, not least CD28, LAT and SLP-76 , which allows the aggregation of signalling complexes around these proteins. Phosphorylated LAT recruits SLP-76 to

4588-717: The CD4 glycoprotein on their surfaces. Helper T cells become activated when they are presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells (APCs). Once activated, they divide rapidly and secrete cytokines that regulate or assist the immune response. These cells can differentiate into one of several subtypes, which have different roles. Cytokines direct T cells into particular subtypes. Cytotoxic T cells (T C cells, CTLs, T-killer cells, killer T cells) destroy virus-infected cells and tumor cells, and are also implicated in transplant rejection. These cells are defined by

4712-636: The NF-κB pathway . DAG activates PKC-θ, which then phosphorylates CARMA1, causing it to unfold and function as a scaffold. The cytosolic domains bind an adapter BCL10 via CARD (Caspase activation and recruitment domains) domains; that then binds TRAF6, which is ubiquitinated at K63. This form of ubiquitination does not lead to degradation of target proteins. Rather, it serves to recruit NEMO, IKKα and -β, and TAB1-2/ TAK1. TAK 1 phosphorylates IKK-β, which then phosphorylates IκB allowing for K48 ubiquitination: leads to proteasomal degradation. Rel A and p50 can then enter

4836-532: The PI3K pathway generating PIP3 at the plasma membrane and recruiting PH domain containing signaling molecules like PDK1 that are essential for the activation of PKC-θ , and eventual IL-2 production. Optimal CD8 T cell response relies on CD4 signalling. CD4 cells are useful in the initial antigenic activation of naive CD8 T cells, and sustaining memory CD8 T cells in the aftermath of an acute infection. Therefore, activation of CD4 T cells can be beneficial to

4960-683: The T-Cell Activation in Space (TCAS) experiment was launched to the International Space Station on the SpaceX CRS-3 mission to study how "deficiencies in the human immune system are affected by a microgravity environment". T cell activation is modulated by reactive oxygen species . A unique feature of T cells is their ability to discriminate between healthy and abnormal (e.g. infected or cancerous) cells in

5084-483: The 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 is yet to be published. Gamma delta T cells (γδ T cells) represent a small subset of T cells which possess a γδ TCR rather than the αβ TCR on the cell surface. The majority of T cells express αβ TCR chains. This group of T cells

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5208-486: The cell cycle . External to the inner plate is the outer plate , which is composed mostly of proteins. This structure is assembled on the surface of the chromosomes only after the nuclear envelope breaks down. The outer plate in vertebrate kinetochores contains about 20 anchoring sites for MTs (+) ends (named kMTs, after kinetochore MTs ), whereas a kinetochore's outer plate in yeast ( Saccharomyces cerevisiae ) contains only one anchoring site. The outermost domain in

5332-463: The centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis . The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore (= movement place) has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as

5456-462: The conifers and flowering plants . Instead, the nuclear envelope itself appears to function as the main MTOC for microtubule nucleation and spindle organization during plant cell mitosis. The MTOC reorients itself during signal transduction, primarily during wound repair or immune responses. The MTOC is relocalized to a position between the edge of the cell and the nucleus in cells like macrophages, fibroblasts, and endothelial cells. Organelles like

5580-566: The origin recognition complex -ORC- implicated in DNA replication initiation during S phase ) is also localized at kinetochores during mitosis in human cells; in agreement with this localization, some studies indicate that Orc2 in yeast is implicated in sister chromatids cohesion, and when it is eliminated from the cell, spindle checkpoint activation ensues. Some other ORC components (such orc5 in S. pombe ) have been also found to participate in cohesion. However, ORC proteins seem to participate in

5704-502: The thymus . After migration to the thymus, the precursor cells mature into several distinct types of T cells. T cell differentiation also continues after they have left the thymus. Groups of specific, differentiated T cell subtypes have a variety of important functions in controlling and shaping the immune response . One of these functions is immune-mediated cell death, and it is carried out by two major subtypes: CD8 "killer" (cytotoxic) and CD4 "helper" T cells. (These are named for

5828-568: The CD4 T cells, function as "helper cells". Unlike CD8 killer T cells, the CD4 helper T (T H ) cells function by further activating memory B cells and cytotoxic T cells, which leads to a larger immune response. The specific adaptive immune response regulated by the T H cell depends on its subtype (such as T-helper1, T-helper2, T-helper17, regulatory T-cell), which is distinguished by the types of cytokines they secrete. Regulatory T cells are yet another distinct population of T cells that provide

5952-422: The Golgi apparatus aid in the reorientation of the MTOC which can occur rapidly. Transduction signals cause microtubules to grow or contract, as well as cause the centrosome to become motile. The MTOC is located in a perinuclear position and contains the negative ends of microtubules while the positive ends grow rapidly towards the edge of the cell. The Golgi apparatus reorients along with the MTOC, and together cause

6076-660: The MTs in the spindle attach to one kinetochore. There are MTs that extend from one centrosome to the other (and they are responsible for spindle length) and some shorter ones are interdigitated between the long MTs. Professor B. Nicklas (Duke University), showed that, if one breaks down the MT-kinetochore attachment using a laser beam , chromatids can no longer move, leading to an abnormal chromosome distribution. These experiments also showed that kinetochores have polarity, and that kinetochore attachment to MTs emanating from one or

6200-442: The Ndc80 complex is essential for stabilization of the kinetochore-microtubule anchoring, required to support the centromeric tension implicated in the establishment of the correct chromosome congression in high eukaryotes . Cells with impaired function of Ndc80 (using RNAi , gene knockout , or antibody microinjection) have abnormally long spindles, lack of tension between sister kinetochores, chromosomes unable to congregate at

6324-562: The Ndc80 complex participates in the regulation of the stable association of Mad1-Mad2 and dynein with kinetochores. Yet the kinetochore associated proteins CENP-A, CENP-C, CENP-E, CENP-H and BubR1 are independent of Ndc80/Hec1. The prolonged arrest in prometaphase observed in cells with low levels of Ndc80/Hec1 depends on Mad2, although these cells show low levels of Mad1, Mad2 and dynein on kinetochores (<10-15% in relation to unattached kinetochores). However, if both Ndc80/Hec1 and Nuf2 levels are reduced, Mad1 and Mad2 completely disappear from

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6448-456: The Ran binding protein called RanBP2/Nup358 . During interphase, these proteins are located at the nuclear pores and participate in the nucleo-cytoplasmic transport. Kinetochore localization of these proteins seem to be functionally significant, because some treatments that increase the levels of Ran-GTP inhibit kinetochore release of Bub1, Bub3, Mad2 and CENP-E. Orc2 (a protein that belongs to

6572-639: The TCR becomes fully operational and the thymocyte becomes a T cell. At the DN2 stage (CD44 CD25 ), cells upregulate the recombination genes RAG1 and RAG2 and re-arrange the TCRβ locus, combining V-D-J recombination and constant region genes in an attempt to create a functional TCRβ chain. As the developing thymocyte progresses through to the DN3 stage (CD44 CD25 ), the thymocyte expresses an invariant α-chain called pre-Tα alongside

6696-449: The TCRβ gene. If the rearranged β-chain successfully pairs with the invariant α-chain, signals are produced which cease rearrangement of the β-chain (and silence the alternate allele). Although these signals require the pre-TCR at the cell surface, they are independent of ligand binding to the pre-TCR. If the chains successfully pair a pre-TCR forms, and the cell downregulates CD25 and is termed

6820-558: The Vγ9 and Vδ2 gene fragments constitute the major γδ T cell population in peripheral blood. These cells are unique in that they specifically and rapidly respond to a set of nonpeptidic phosphorylated isoprenoid precursors, collectively named phosphoantigens , which are produced by virtually all living cells. The most common phosphoantigens from animal and human cells (including cancer cells) are isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMPP). Many microbes produce

6944-497: The action of CD8 T cells. The first signal is provided by binding of the T cell receptor to its cognate peptide presented on MHCII on an APC. MHCII is restricted to so-called professional antigen-presenting cells , like dendritic cells, B cells, and macrophages, to name a few. The peptides presented to CD8 T cells by MHC class I molecules are 8–13 amino acids in length; the peptides presented to CD4 cells by MHC class II molecules are longer, usually 12–25 amino acids in length, as

7068-464: The active compound hydroxy-DMAPP ( HMB-PP ) and corresponding mononucleotide conjugates, in addition to IPP and DMAPP. Plant cells produce both types of phosphoantigens. Drugs activating human Vγ9/Vδ2 T cells comprise synthetic phosphoantigens and aminobisphosphonates , which upregulate endogenous IPP/DMAPP. Activation of CD4 T cells occurs through the simultaneous engagement of the T-cell receptor and

7192-415: The amount of DNA is doubled in each chromosome (while maintaining the same number of chromosomes) in S phase , two sister chromatids are held together by a centromere. Each chromatid has its own kinetochore, which face in opposite directions and attach to opposite poles of the mitotic spindle apparatus. Following the transition from metaphase to anaphase , the sister chromatids separate from each other, and

7316-413: The blood to the thymus, where they engraft: . Henceforth they are known as thymocytes , the immature stage of a T cell. The earliest cells which arrived in the thymus are commonly termed double-negative , as they express neither the CD4 nor CD8 co-receptor. The newly arrived CLP cells are CD4 CD8 CD44 CD25 ckit cells, and are termed early thymic progenitor (ETP) cells. These cells will then undergo

7440-525: The blood, liver, lungs, and mucosa , defending against microbial activity and infection. The MHC class I -like protein, MR1 , is responsible for presenting bacterially-produced vitamin B metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports

7564-407: The body from damage. Sepsis also carries high antigen load and inflammation. In this stage of sepsis T cell exhaustion increases. Currently there are studies aiming to utilize inhibitory receptor blockades in treatment of sepsis. While during infection T cell exhaustion can develop following persistent antigen exposure after graft transplant similar situation arises with alloantigen presence. It

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7688-533: The body. Healthy cells typically express a large number of self derived pMHC on their cell surface and although the T cell antigen receptor can interact with at least a subset of these self pMHC, the T cell generally ignores these healthy cells. However, when these very same cells contain even minute quantities of pathogen derived pMHC, T cells are able to become activated and initiate immune responses. The ability of T cells to ignore healthy cells but respond when these same cells contain pathogen (or cancer) derived pMHC

7812-408: The bone marrow. In some cases, the origin might be the foetal liver during embryonic development . The HSC then differentiate into multipotent progenitors (MPP) which retain the potential to become both myeloid and lymphoid cells . The process of differentiation then proceeds to a common lymphoid progenitor (CLP), which can only differentiate into T, B or NK cells. These CLP cells then migrate via

7936-782: The boundary of the cortex and medulla in the thymus. While in the medulla, they are again presented with a self-antigen presented on the MHC complex of medullary thymic epithelial cells (mTECs). mTECs must be Autoimmune regulator positive (AIRE ) to properly express tissue-specific antigens on their MHC class I peptides. Some mTECs are phagocytosed by thymic dendritic cells ; this makes them AIRE antigen presenting cells (APCs), allowing for presentation of self-antigens on MHC class II molecules (positively selected CD4 cells must interact with these MHC class II molecules, thus APCs, which possess MHC class II, must be present for CD4 T-cell negative selection). Thymocytes that interact too strongly with

8060-407: The cell to seemingly send a polarized signal. In immune responses, upon interaction with a target cell in response to antigen-specific loaded antigen-presenting cells, immune cells, such as the T cells , natural killer cells , and cytotoxic T lymphocytes, localize their MTOCs near the contact zone between the immune cell and the target cell. For T cells, the T cell receptor signaling response causes

8184-422: The cell. To prevent this from happening, there are mechanisms of error detection and correction (as the spindle assembly checkpoint ), whose components reside also on the kinetochores. The movement of one chromatid towards the centrosome is produced primarily by MT depolymerization in the binding site with the kinetochore. These movements require also force generation, involving molecular motors likewise located on

8308-506: The cells that are produced by a given cause (typically, but not necessarily, chronic exposure to an antigen). Finally, the third approach primarily defines as exhausted the cells that present the same molecular markers (typically, programmed cell death protein 1 [PD-1])." Dysfunctional T cells are characterized by progressive loss of function, changes in transcriptional profiles and sustained expression of inhibitory receptors. At first, cells lose their ability to produce IL-2 and TNFα , which

8432-502: The centromeres during mitosis, and consequently sister chromatids separate synchronically before anaphase initiates, which triggers a long mitotic arrest. On the other hand, Dasso and collaborators have found that proteins involved in the Ran cycle can be detected on kinetochores during mitosis: RanGAP1 (a GTPase activating protein which stimulates the conversion of Ran-GTP in Ran-GDP) and

8556-477: The centrosome, these MTOCs stabilize and give direction to the microtubules, in this case to allow unidirectional movement of the cilium itself, rather than vesicles moving along it. In yeasts and some algae , the MTOC is embedded into the nuclear envelope as a spindle pole body. Centrioles do not exist in the MTOCs of yeast and fungi. In these organisms, the nuclear envelope does not break down during mitosis and

8680-427: The cessation of mitosis contains one primary MTOC. Before cell division begins, the interphase MTOC replicates to form two distinct MTOCs (now typically referred to as centrosomes). During cell division, these centrosomes move to opposite ends of the cell and nucleate microtubules to help form the mitotic/meiotic spindle. If the MTOC does not replicate, the spindle cannot form, and mitosis ceases prematurely. γ-tubulin

8804-416: The components of this complex show loss of the kinetochore-microtubule connection, although kinetochore structure is not completely lost. Yet mutants in which kinetochore structure is lost (for instance Ndc10 mutants in yeast ) are deficient both in the connection to microtubules and in the ability to activate the spindle checkpoint , probably because kinetochores work as a platform in which the components of

8928-554: The constitutive protein Ndc10p and members of the Ndc80 and Dam1-DASH-DDD complexes. Phosphorylation of Ndc80 complex components produces destabilization of kMTs anchoring. It has been proposed that Aurora B localization is important for its function: as it is located in the inner region of the kinetochore (in the centromeric heterochromatin), when the centromeric tension is established sister kinetochores separate, and Aurora B cannot reach its substrates, so that kMTs are stabilized. Aurora B

9052-627: The context of an MHC molecule on the surface of a professional antigen presenting cell (e.g. a dendritic cell). Appropriate co-stimulation must be present at the time of antigen encounter for this process to occur. Historically, memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers (see below). Subsequently, numerous new populations of memory T cells were discovered including tissue-resident memory T (Trm) cells, stem memory TSCM cells, and virtual memory T cells. The single unifying theme for all memory T cell subtypes

9176-941: The context of infections and cancer. Furthermore, these T cell subsets are being translated into many therapies against malignancies such as leukemia, for example. Natural killer T cells (NKT cells – not to be confused with natural killer cells of the innate immune system) bridge the adaptive immune system with the innate immune system . Unlike conventional T cells that recognize protein peptide antigens presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigens presented by CD1d . Once activated, these cells can perform functions ascribed to both helper and cytotoxic T cells: cytokine production and release of cytolytic/cell killing molecules. They are also able to recognize and eliminate some tumor cells and cells infected with herpes viruses. Mucosal associated invariant T (MAIT) cells display innate , effector-like qualities. In humans, MAIT cells are found in

9300-525: The course of exhaustion because longer exposure time and higher viral load increases the severity of T cell exhaustion. At least 2–4 weeks exposure is needed to establish exhaustion. Another factor able to induce exhaustion are inhibitory receptors including programmed cell death protein 1 (PD1), CTLA-4 , T cell membrane protein-3 (TIM3), and lymphocyte activation gene 3 protein (LAG3). Soluble molecules such as cytokines IL-10 or TGF-β are also able to trigger exhaustion. Last known factors that can play

9424-552: The critical mechanism of tolerance , whereby immune cells are able to distinguish invading cells from "self". This prevents immune cells from inappropriately reacting against one's own cells, known as an " autoimmune " response. For this reason, these regulatory T cells have also been called "suppressor" T cells. These same regulatory T cells can also be co-opted by cancer cells to prevent the recognition of, and an immune response against, tumor cells. All T cells originate from c-kit Sca1 haematopoietic stem cells (HSC) which reside in

9548-468: The cytoplasm, centrioles can gather during differentiation to become MTOCs. They can also be focused around a centrosome as a single MTOC, though centrosomes can work as an MTOC absent of centrioles. Most animal cells have one MTOC during interphase , usually located near the nucleus , and generally associated closely with the Golgi apparatus . The MTOC is made up of a pair of centrioles at its center, and

9672-426: The cytosol from the extracellular space. This aggregated cytosolic calcium 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 the transcription of a pleiotropic set of genes, most notable, IL-2, a cytokine that promotes long-term proliferation of activated T cells. PLC-γ can also initiate

9796-599: The data obtained so far. The first protein to be assembled on the kinetochore is CENP-A ( Cse4 in Saccharomyces cerevisiae ). This protein is a specialized isoform of histone H3. CENP-A is required for incorporation of the inner kinetochore proteins CENP-C , CENP-H and CENP-I/MIS6 . The relation of these proteins in the CENP-A-dependent pathway is not completely defined. For instance, CENP-C localization requires CENP-H in chicken cells, but it

9920-413: The dynamic instability of the kMTs (+) end, and it is partially controlled by the tension present at the kinetochore. In mammalian cultured cells, a low tension at kinetochores promotes change towards kMTs depolymerization, and high tension promotes change towards kMTs polymerization. Kinetochore proteins and proteins binding to MTs (+) end (collectively called +TIPs) regulate kinetochore movement through

10044-429: The end of G2 phase in cultured mammalian cells. These early kinetochores show a mature laminar structure before the nuclear envelope breaks down. The molecular pathway for kinetochore assembly in higher eukaryotes has been studied using gene knockouts in mice and in cultured chicken cells, as well as using RNA interference (RNAi) in C. elegans , Drosophila and human cells, yet no simple linear route can describe

10168-407: The ends of the binding cleft of the MHC class II molecule are open. The second signal comes from co-stimulation, in which surface receptors on the APC are induced by a relatively small number of stimuli, usually products of pathogens, but sometimes breakdown products of cells, such as necrotic -bodies or heat shock proteins . The only co-stimulatory receptor expressed constitutively by naive T cells

10292-599: The expression of the CD8 protein on their cell surface. Cytotoxic T cells recognize their targets by binding to short peptides (8-11 amino acids in length) associated with MHC class I molecules, present on the surface of all nucleated cells. Cytotoxic T cells also produce the key cytokines IL-2 and IFNγ. These cytokines influence the effector functions of other cells, in particular macrophages and NK cells. Antigen-naive T cells expand and differentiate into memory and effector T cells after they encounter their cognate antigen within

10416-814: The expression of the transcription factor FOXP3 which can be used to identify the cells. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX . Several other types of T cells have suppressive activity, but do not express FOXP3 constitutively. These include Tr1 and Th3 cells, which are thought to originate during an immune response and act by producing suppressive molecules. Tr1 cells are associated with IL-10, and Th3 cells are associated with TGF-beta . Recently, Th17 cells have been added to this list. Innate-like T cells or unconventional T cells represent some subsets of T cells that behave differently in immunity. They trigger rapid immune responses, regardless of

10540-599: The frequency at which this happens are important questions, because this mechanism may contribute not only to the initial formation of kMTs, but also to the way in which kinetochores correct defective anchoring of MTs and regulate the movement along kMTs. MTs associated to kinetochores present special features: compared to free MTs, kMTs are much more resistant to cold-induced depolymerization, high hydrostatic pressures or calcium exposure. Furthermore, kMTs are recycled much more slowly than astral MTs and spindle MTs with free (+) ends, and if kMTs are released from kinetochores using

10664-418: The function of this complex has been abolished by dominant negative mutants, RNAi , antibody microinjection or using selective drugs, accumulate errors in chromosome anchoring. Many studies have shown that Aurora B is required to destabilize incorrect anchoring kinetochore-MT, favoring the generation of amphitelic connections. Aurora B homolog in yeast (Ipl1p) phosphorilates some kinetochore proteins, such as

10788-405: The genetic information stored in the chromosomes, in the process termed DNA replication . At the end of this process, each chromosome includes two sister chromatids , which are two complete and identical DNA molecules. Both chromatids remain associated by cohesin complexes until anaphase, when chromosome segregation occurs. If chromosome segregation happens correctly, each daughter cell receives

10912-407: The host. β-selection is the first checkpoint, where thymocytes that are able to form a functional pre-TCR (with an invariant alpha chain and a functional beta chain) are allowed to continue development in the thymus. Next, positive selection checks that thymocytes have successfully rearranged their TCRα locus and are capable of recognizing MHC molecules with appropriate affinity. Negative selection in

11036-438: 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 . T cells are born from hematopoietic stem cells , found in the bone marrow . Developing T cells then migrate to the thymus gland to develop (or mature). T cells derive their name from

11160-451: The individual kinetochores on each chromatid drive their movement to the spindle poles that will define the two new daughter cells. The kinetochore is therefore essential for the chromosome segregation that is classically associated with mitosis and meiosis. The kinetochore contains two regions: Even the simplest kinetochores consist of more than 19 different proteins. Many of these proteins are conserved between eukaryotic species, including

11284-498: The initial capture of MTs is CENP-E; this is a high molecular weight kinesin associated with the fibrous corona at mammalian kinetochores from prometaphase until anaphase. In cells with low levels of CENP-E, chromosomes lack this protein at their kinetochores, which quite often are defective in their ability to congress at the metaphase plate. In this case, some chromosomes may remain chronically mono-oriented (anchored to only one pole), although most chromosomes may congress correctly at

11408-493: The integrity of meiotic kinetochore is essential for meiosis specific events such as pairing of homologous chromosomes, sister kinetochore monoorientation, protection of centromeric cohesin and spindle-pole body cohesion and duplication. The kinetochore is composed of several layers, observed initially by conventional fixation and staining methods of electron microscopy , (reviewed by C. Rieder in 1982 ) and more recently by rapid freezing and substitution. The deepest layer in

11532-464: The kMTs (+) end dynamics regulation. However, the kinetochore-microtubule interface is highly dynamic, and some of these proteins seem to be bona fide components of both structures. Two groups of proteins seem to be particularly important: kinesins which work like depolymerases, such as KinI kinesins; and proteins bound to MT (+) ends, +TIPs, promoting polymerization, perhaps antagonizing the depolymerases effect. T cells T cells are one of

11656-471: The kinetochore forms a fibrous corona, which can be visualized by conventional microscopy , yet only in the absence of MTs. This corona is formed by a dynamic network of resident and temporary proteins implicated in the spindle checkpoint , in microtubule anchoring, and in the regulation of chromosome behavior. During mitosis, each sister chromatid forming the complete chromosome has its own kinetochore. Distinct sister kinetochores can be observed at first at

11780-433: The kinetochore is the inner plate , which is organized on a chromatin structure containing nucleosomes presenting a specialized histone (named CENP-A , which substitutes histone H3 in this region), auxiliary proteins, and DNA. DNA organization in the centromere ( satellite DNA ) is one of the least understood aspects of vertebrate kinetochores. The inner plate appears like a discrete heterochromatin domain throughout

11904-528: The kinetochores and the spindle checkpoint is inactivated. Shugoshin (Sgo1, MEI-S332 in Drosophila melanogaster ) are centromeric proteins which are essential to maintain cohesin bound to centromeres until anaphase. The human homolog, hsSgo1, associates with centromeres during prophase and disappears when anaphase starts. When Shugoshin levels are reduced by RNAi in HeLa cells, cohesin cannot remain on

12028-411: The kinetochores. During the synthesis phase (S phase) in the cell cycle , the centrosome starts to duplicate. Just at the beginning of mitosis, both centrioles in each centrosome reach their maximal length, centrosomes recruit additional material and their nucleation capacity for microtubules increases. As mitosis progresses, both centrosomes separate to establish the mitotic spindle. In this way,

12152-572: The known structure during mitosis, which confirms the kinetochore as one of the most complex cellular substructures. Consistently, a comprehensive literature survey indicated that there had been at least 196 human proteins already experimentally shown to be localized at kinetochores. The number of microtubules attached to one kinetochore is variable: in Saccharomyces cerevisiae only one MT binds each kinetochore, whereas in mammals there can be 15–35 MTs bound to each kinetochore. However, not all

12276-419: The major histocompatibility complex (MHC) expression, unlike their conventional counterparts (CD4 T helper cells and CD8 cytotoxic T cells), which are dependent on the recognition of peptide antigens in the context of the MHC molecule. Overall, there are three large populations of unconventional T cells: NKT cells, MAIT cells, and gammadelta T cells. Now, their functional roles are already being well established in

12400-464: The medulla then eliminates thymocytes that bind too strongly to self-antigens expressed on MHC molecules. These selection processes allow for tolerance of self by the immune system. Typical naive T cells that leave the thymus (via the corticomedullary junction) are self-restricted, self-tolerant, and single positive. About 98% of thymocytes die during the development processes in the thymus by failing either positive selection or negative selection, whereas

12524-458: The membrane, where it can then bring in PLC-γ , VAV1 , Itk and potentially PI3K . PLC-γ cleaves PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries diacylglycerol ( DAG ), inositol-1,4,5-trisphosphate ( IP3 ); PI3K also acts on PIP2, phosphorylating it to produce phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs. Most important in T cells

12648-403: The metaphase plate and few or any associated kMTs. There is a variety of strong support for the ability of the Ndc80 complex to directly associate with microtubules and form the core conserved component of the kinetochore-microtubule interface. However, formation of robust kinetochore-microtubule interactions may also require the function of additional proteins. In yeast, this connection requires

12772-518: The metaphase plate, all checkpoint proteins are released from the kinetochore. The disappearance of the checkpoint proteins out of the kinetochores indicates the moment when the chromosome has reached the metaphase plate and is under bipolar tension. At this moment, the checkpoint proteins that bind to and inhibit Cdc20 (Mad1-Mad2 and BubR1), release Cdc20, which binds and activates APC/C , and this complex triggers sister chromatids separation and consequently anaphase entry. Several studies indicate that

12896-420: The metaphase plate. It is widely accepted that the kMTs fiber (the bundle of microtubules bound to the kinetochore) is originated by the capture of MTs polymerized at the centrosomes and spindle poles in mammalian cultured cells. However, MTs directly polymerized at kinetochores might also contribute significantly. The manner in which the centromeric region or kinetochore initiates the formation of kMTs and

13020-524: The nucleus and bind the NF-κB response element. This coupled with NFAT signaling allows for complete activation of the IL-2 gene. While in most cases activation is dependent on TCR recognition of antigen, alternative pathways for activation have been described. For example, cytotoxic T cells have been shown to become activated when targeted by other CD8 T cells leading to tolerization of the latter. In spring 2014,

13144-404: The other 2% survive and leave the thymus to become mature immunocompetent T cells. The thymus contributes fewer cells as a person ages. As the thymus shrinks by about 3% a year throughout middle age, a corresponding fall in the thymic production of naive T cells occurs, leaving peripheral T cell expansion and regeneration to play a greater role in protecting older people. T cells are grouped into

13268-503: The other centrosome will depend on its orientation. This specificity guarantees that only one chromatid will move to each spindle side, thus ensuring the correct distribution of the genetic material. Thus, one of the basic functions of the kinetochore is the MT attachment to the spindle, which is essential to correctly segregate sister chromatids. If anchoring is incorrect, errors may ensue, generating aneuploidy , with catastrophic consequences for

13392-414: The other hand, microtubules are metastable polymers made of α- and β- tubulin , alternating between growing and shrinking phases, a phenomenon known as dynamic instability . MTs are highly dynamic structures, whose behavior is integrated with kinetochore function to control chromosome movement and segregation. It has also been reported that the kinetochore organization differs between mitosis and meiosis and

13516-406: The pole ( poleward ) or inversed ( anti-poleward ), which are coupled with alternating states of kMTs depolymerization and polymerization, respectively. This kinetochore bi-stability seem to be part of a mechanism to align the chromosomes at the equator of the spindle without losing the mechanic connection between kinetochores and spindle poles. It is thought that kinetochore bi-stability is based upon

13640-412: The pole generating that microtubule. This movement is probably mediated by the motor activity towards the "minus" (-) of the motor protein cytoplasmic dynein, which is very concentrated in the kinetochores not anchored to MTs. The movement towards the pole is slowed down as far as kinetochores acquire kMTs (MTs anchored to kinetochores) and the movement becomes directed by changes in kMTs length. Dynein

13764-400: The presence of the cell surface proteins CD8 or CD4 .) CD8 T cells, also known as "killer T cells", are cytotoxic – this means that they are able to directly kill virus-infected cells, as well as cancer cells. CD8 T cells are also able to use small signalling proteins, known as cytokines , to recruit other types of cells when mounting an immune response. A different population of T cells,

13888-422: The presence of the complex Dam1 -DASH-DDD. Some members of this complex bind directly to MTs, whereas some others bind to the Ndc80 complex. This means that the complex Dam1-DASH-DDD might be an essential adapter between kinetochores and microtubules. However, in animals an equivalent complex has not been identified, and this question remains under intense investigation. During S-Phase , the cell duplicates all

14012-415: The process of developing a functional TCR. The TCR consists of two major components, the alpha and beta chains. These both contain random elements designed to produce a wide variety of different TCRs, but due to this huge variety they must be tested to make sure they work at all. First, the thymocytes attempt to create a functional beta chain, testing it against a 'mock' alpha chain. Then they attempt to create

14136-462: The reorientation of the MTOC by microtubules shortening to bring the MTOC to the site of interaction of the T cell receptor. Kinetochores A kinetochore ( / k ɪ ˈ n ɛ t ə k ɔːr / , /- ˈ n iː t ə k ɔːr / ) is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on

14260-456: The response are assembled. The Ndc80 complex is highly conserved and it has been identified in S. pombe , C. elegans , Xenopus , chicken and humans. Studies on Hec1 ( highly expressed in cancer cells 1 ), the human homolog of Ndc80p, show that it is important for correct chromosome congression and mitotic progression, and that it interacts with components of the cohesin and condensin complexes. Different laboratories have shown that

14384-411: The second kinetochore becomes attached to the microtubules emanating from the opposing pole, in such a way that chromosomes are now bi-oriented , one fundamental configuration (also termed amphitelic ) to ensure the correct segregation of both chromatids when the cell will divide. When just one microtubule is anchored to one kinetochore, it starts a rapid movement of the associated chromosome towards

14508-416: The self-antigen receive an apoptotic signal that leads to cell death. However, some of these cells are selected to become Treg cells. The remaining cells exit the thymus as mature naive T cells , also known as recent thymic emigrants. This process is an important component of central tolerance and serves to prevent the formation of self-reactive T cells that are capable of inducing autoimmune diseases in

14632-505: The spindle checkpoint components are assembled on the kinetochore in high concentrations in the absence of microtubules, and their concentrations decrease as the number of microtubules attached to the kinetochore increases. At metaphase, CENP-E , Bub3 and Bub1 levels decreases 3 to 4 fold as compared to the levels at unattached kinetochores, whereas the levels of dynein/dynactin , Mad1 , Mad2 and BubR1 decrease >10-100 fold. Thus at metaphase, when all chromosomes are aligned at

14756-554: The spindle checkpoint. In contrast, the merotelic configuration is not detected by this control mechanism. However, most of these errors are detected and corrected before the cell enters in anaphase. A key factor in the correction of these anchoring errors is the chromosomal passenger complex, which includes the kinase protein Aurora B, its target and activating subunit INCENP and two other subunits, Survivin and Borealin/Dasra B (reviewed by Adams and collaborators in 2001 ). Cells in which

14880-441: The spindle in a mitotic cell has two poles emanating microtubules. Microtubules are long proteic filaments with asymmetric extremes, a "minus"(-) end relatively stable next to the centrosome, and a "plus"(+) end enduring alternate phases of growing-shrinking, exploring the center of the cell. During this searching process, a microtubule may encounter and capture a chromosome through the kinetochore. Microtubules that find and attach

15004-491: The spindle pole body serves to connect cytoplasmic with nuclear microtubules. The disc-shaped spindle pole body is organized into three layers: the central plaque, inner plaque, and outer plaque. The central plaque is embedded in the membrane, while the inner plaque is an amorphous intranuclear layer, and the outer plaque is the layer located in the cytoplasm. Plant cells lack centrioles or spindle pole bodies except in their flagellate male gametes, and they are entirely absent in

15128-539: The surface of cortical epithelial cells. Only thymocytes that interact well with MHC-I or MHC-II will receive a vital "survival signal", while those that cannot interact strongly enough will receive no signal and die from neglect . This process ensures that the surviving thymocytes will have an 'MHC affinity' that means they will exhibit stronger binding affinity for specific MHC alleles in that organism. The vast majority of developing thymocytes will not pass positive selection, and die during this process. A thymocyte's fate

15252-477: The tension between sister kinetochores and activate the spindle checkpoint to arrest the cell cycle when either of these is absent. The actual set of genes essential for kinetochore function varies from one species to another. Kinetochore functions include anchoring of chromosomes to MTs in the spindle, verification of anchoring, activation of the spindle checkpoint and participation in the generation of force to propel chromosome movement during cell division. On

15376-663: Was shown that T cell response diminishes over time after kidney transplant. These data suggest T cell exhaustion plays an important role in tolerance of a graft mainly by depletion of alloreactive CD8 T cells. Several studies showed positive effect of chronic infection on graft acceptance and its long-term survival mediated partly by T cell exhaustion. It was also shown that recipient T cell exhaustion provides sufficient conditions for NK cell transfer. While there are data showing that induction of T cell exhaustion can be beneficial for transplantation it also carries disadvantages among which can be counted increased number of infections and

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