File Name: activation of b and t lymphocytes .zip
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As their name suggests, they "help" the activity of other immune cells by releasing cytokines , small protein mediators that alter the behavior of target cells that express receptors for those cytokines.
The fate of T and B lymphocytes, the key cells that direct the adaptive immune response, is regulated by a diverse network of signal transduction pathways. The T- and B-cell antigen receptors are coupled to intracellular tyrosine kinases and adaptor molecules to control the metabolism of inositol phospholipids and calcium release. Lymphocyte activation is modulated by costimulatory molecules and cytokines that elicit intracellular signaling that is integrated with the antigen-receptor-controlled pathways.
The adaptive immune response is directed by B and T lymphocytes. These cells express specific receptors that recognize pathogen-derived antigens: the B-cell antigen receptor BCR and the T-cell antigen receptor TCR , respectively.
T cells have multiple roles in adaptive immune responses. In this context, peripheral T cells can be subdivided on the basis of whether they express CD8 or CD4, receptors that recognize class I and class II major histocompatibility complex MHC molecules, respectively. The paradigm of the adaptive immune response is that a primary response to an antigen causes clonal expansion of antigen-reactive T or B cells and produces a large number of effector lymphocytes that cause clearance of the pathogen.
Once the pathogen is cleared there is a contraction phase of the immune response characterized by loss of effector lymphocytes and the emergence of long-lived memory cells capable of mounting rapid secondary responses to reinfection with the original pathogen.
The proliferation and differentiation of mature lymphocytes in adaptive immune responses are directed by antigen receptors, costimulatory molecules, adhesion molecules, cytokines, and chemokines. These extrinsic stimuli are coupled to a diverse network of signal transduction pathways that control the transcriptional and metabolic programs that determine lymphocyte function. At the core of lymphocyte signal transduction is the regulated metabolism of inositol phospholipids and the resultant production of inositol polyphosphates and lipids such as polyunsaturated diacylglycerols DAGs.
These second messengers direct the activity of protein and lipid kinases and guanine-nucleotide-binding proteins that control lymphocyte proliferation, differentiation, and effector function. Below, I outline both the unique and the conserved aspects of signaling in lymphocytes, focusing on signaling pathways controlled by antigen receptors and how these responses are subsequently shaped and modulated by cytokines and chemokines. The TCR and BCR are multiprotein complexes comprising subunits containing highly variable antigen-binding regions linked noncovalently to invariant signal transduction subunits.
In both cases, rearrangements of the DNA sequences that encode the antigen-binding region create a diversity in antigen-receptor structures. A key feature of T- and B-cell populations is that each individual lymphocyte will express multiple copies of a unique antigen receptor with a single antigen specificity defined by three complementarity-determining regions [CDRs]. It is the selectivity of antigen receptors that underpins immune specificity by ensuring that only those lymphocytes that recognize a specific pathogen are activated by it.
CD3 antigens also transmit signals into the cell across the plasma membrane. This is compared with to a minimal estimate of 10 11 BCR complexes. These couple the TCR to intracellular tyrosine kinases see below. ITAM motifs are a defining feature of antigen-receptor complexes.
For example, mast cells comprise an important group of lymphocytes whose fate is determined by antigen-specific immunoglobulin. These cells respond to antigen because they express a high-affinity receptor for IgE. When both tyrosine residues are phosphorylated, the ITAM forms a high-affinity binding site for Syk-family tyrosine kinases; generally in T cells this is Zap Wang et al.
Antigen-receptor control of Syk-family tyrosine kinases is fundamental for lymphocyte activation and underpins the ability of antigen receptors to transduce signals from pathogen-derived antigens to the interior of lymphocytes Mocsai et al. How the Src-family kinases such as Lck are regulated is central to antigen-receptor signal transduction Salmond et al. The activity of Lck is regulated by phosphorylation and dephosphorylation of a carboxy-terminal tyrosine Y by the ubiquitously expressed kinase carboxy-terminal Src kinase CSK , as well as autophosphorylation of the activation loop tyrosine residue, Y Phosphorylated Y forms an intramolecular binding site for the Lck SH2 domain, thereby locking the kinase into an autoinhibited state.
The key to initiating the activation of Lck and its relatives is to dephosphorylate the carboxy-terminal tyrosine and relieve autoinhibition of the kinase.
This is mediated by transmembrane-receptor-like tyrosine phosphatases, such as CD45 and CD Hermiston et al. Hence in T cells, the Lck activation threshold is set by the balanced activity of the kinase-phosphatase pair CSK, which phosphorylates Y, and CD45, which dephosphorylates this residue Zikherman et al. It is frequently assumed that triggering antigen receptors stimulates Src kinase family activity, and antigen receptors are often depicted as molecular switches that are either on or off.
In reality, antigen receptors are always signaling and it is the intensity of the signal that changes. The assembly of antigen receptors at the plasma membrane is thus proposed to mediate low-level signaling and the engagement with high-affinity ligands antigen or antigen—MHC increases the intensity.
Indeed Src-family kinases such as Lck are constitutively active before antigen-receptor engagement and cause low-level ITAM phosphorylation Nika et al. The levels of ITAM phosphorylation are limited by tyrosine phosphatases, and the increases in ITAM phosphorylation that follow antigen-receptor engagement probably result from spatial constraints on the ITAM-phosphatase interaction van der Merwe and Dushek How are these spatial constraints regulated to explain how ligand occupancy triggers TCR signaling?
Surprisingly, we do not know, although there is no shortage of theories. Current models range from the ligand-induced conformational change to the idea that the TCR is a mechanosensor that converts the mechanical energy generated by antigen binding into a biochemical signal Kim et al.
One other idea well supported by experimental data is that binding of the TCR to peptide-MHC complexes on the surface ofAPCs causes spatial segregation of TCR complexes which have small ectodomains away from receptor tyrosine phosphatases such as CD45 and CD which have very large ectodomains.
This might locally perturb the kinase—phosphatase balance sufficiently to favor ITAM phosphorylation and Zap recruitment van der Merwe and Davis ; van der Merwe and Dushek Note that the MHC-binding coreceptors CD4 and CD8 are also thought to play a role in perturbing the kinase-phosphatase balance in localized areas of the T-cell membrane.
However, the cytoplasmic domains of CD4 and CD8 constitutively bind Lck and hence facilitate the recruitment of this kinase to ligand-engaged TCR complexes Artyomov et al. In quiescent B cells, the BCR may exist in an oligomeric autoinhibited state, and ligand occupancy could drive the dissociation of these oligomers into monomers that interact more effectively with downstream tyrosine kinases Yang and Reth a , b. This receptor binds IgE but is only effectively triggered when antigen oligomerizes the receptor Beaven and Metzger LAT is an integral membrane protein with a cytoplasmic tail containing nine tyrosine residues.
When phosphorylated, these act as docking sites for effector enzymes containing SH2 domains. SLP contains three key tyrosine residues, a central SH3-binding proline-rich domain and a carboxy-terminal SH2 domain. Signaling downstream from immune receptors bearing immunoreceptor tyrosine-based activation motifs ITAMs; yellow rectangles. This creates docking sites for the recruitment and activation of the tyrosine kinases Zap and Syk.
These in turn phosphorylate adaptor complexes that recruit numerous additional signaling molecules that control phospholipid, calcium, small G protein, and kinase signaling. A major function for antigen-receptor-coupled tyrosine kinases and adaptors is to regulate intracellular calcium levels and control DAG-mediated signaling Oh-hora and Rao ; Matthews and Cantrell This in turn triggers calcium entry across the plasma membrane via activation of highly selective store-operated calcium-release-activated calcium CRAC channels.
There they bind to the CRAC channel protein Orai1, which activates the channels to allow entry of extracellular calcium to promote a sustained increase in intracellular calcium levels. This coupling of antigen receptors to CRAC channels allows lymphocytes to sustain high levels of intracellular calcium concentrations during an immune response Hogan et al.
The best-studied role for calcium signaling in both B and T lymphocytes, however, is control of calcineurin also known as protein phosphatase 2B, PP2B , a protein phosphatase that controls the intracellular localization of members of the NFAT nuclear factor of activated T cells family of transcription factors Im and Rao ; Muller and Rao This phosphorylation of NFATs causes their nuclear exclusion as a result of binding to proteins, thus maintaining them inactive in the cytosol.
NFATs remain inactive until triggering of antigen receptors raises intracellular free calcium levels, which activates calcineurin, which then dephosphorylates NFATs, allowing their translocation to the nucleus. In the nucleus, NFATs form complexes with other transcription factors, bind to target genes and modulate gene transcription. Nevertheless, the rate-limiting step for NFAT activation is antigen-receptor-regulated increases in intracellular calcium and the resultant activation of calcineurin.
These are potent T-cell immunosuppressants used for the prevention of organ transplant rejection and for the treatment of chronic T-cell-mediated autoimmune diseases, such as ectopic eczema. Multiple species of DAG are produced as intermediates in phospholipid resynthesis pathways.
Consequently, quiescent lymphocytes have high levels of DAG before immune activation. They are important regulators of lymphocyte transcriptional programs and, in particular, control expression of genes encoding cytokines and cytokine receptors.
These sites are substrates for both conventional and novel PKCs, and their phosphorylation is essential for efficient TCR-induced cytokine production and for optimal antibody production by B lymphocytes.
The coordination of integrin-mediated cell adhesion by PKC and GTPases is essential to allow T cells, B cells, and natural killer NK cells to form tight contacts with APCs or target cells via a structure known as the immunological synapse Dustin et al.
B cells can also form immunological synapses with APCs in a process that potentiates antigen binding and processing of even membrane-tethered antigens Harwood and Batista Immunological synapses are highly ordered structures characterized by the segregation of receptors and signaling molecules into distinct areas known as supramolecular activation clusters SMACs.
Stable immune synapses are arranged in concentric zones: antigen receptors accumulate in the center cSMAC , whereas integrins segregate to the periphery pSMAC. One common misconception is that the immune synapse is involved in the initiation of antigen-receptor signaling. The reality is that immune synapses are formed as a downstream consequence of antigen-receptor engagement.
Immunological synapses provide a focus for DAG signaling following antigen-receptor engagement Spitaler et al. Moreover, formation of immunological synapses is associated with the polarization of the microtubule-organizing center MTOC toward the target cell. The reorientation of the MTOC controls the ability of lymphocytes to direct cytokine secretion and to direct the exocytosis of secretory or lytic granules.
For example, in cytotoxic T cells the immunological synapse directs the secretion of the granules that contain cytolytic effector molecules such as perforin and granzymes toward the target cell Jenkins and Griffiths In quiescent lymphocytes Ras GTPases are predominantly inactive. Engagement of antigen receptors stimulates Ras proteins to accumulate in a GTP-bound state. It thus binds constitutively to the SH3 domains of the adaptor Grb2 and is recruited to the plasma membrane when the SH2 domain of Grb2 binds to tyrosine-phosphorylated adaptors such as LAT in T cells or Shc in B cells.
These phosphorylate and regulate a number of key substrates, including the ternary complex factor TCF subfamily of ETS-domain transcription factors. The activated carboxy-terminal catalytic domain of RSK then phosphorylates S intramolecularly to create a docking site for the kinase PDK1, which then phosphorylates S in the amino-terminal RSK kinase domain, thereby activating the enzyme Finlay and Cantrell a.
Flow cytometric-based assays that assess ERK activity at the single-cell level have shown that, when lymphocytes respond to an increasing strength of antigen-receptor stimulus, ERK activation is a digital all or nothing rather than an analog response Chakraborty et al. In this digital response, the frequency of cells within a population that activate ERK changes, each cell activating it to an equivalent level.
This means, in practice, that even a strong antigen-receptor stimulus can only trigger a proportion of lymphocytes to activate ERKs at any one time. The digital nature of this ERK response creates signaling heterogeneity within the responding lymphocyte population.
Lymphocyte responses both prior and subsequent to antigen-receptor engagement are modulated by multiple costimulatory and coinhibitory receptors. Signaling via Toll-like receptors TLRs is also a major factor influencing the fate of lymphocytes during an immune response.
Because T and B lymphocytes respond to antigens presented to them by APCs, lymphocyte activation can be regulated by the adhesion molecules and costimulatory molecules expressed by the APC.
Note also that many of the cytokines that control lymphocyte fate are produced in response to TLR-mediated activation of dendritic cells and macrophages Newton and Dixit Hence, the nature of the pathogen challenge to the innate immune system, and the resultant cytokine milieu modulate the adaptive immune response.
A full review of lymphocyte regulation by costimulatory factors is beyond our scope here but there are some general themes. Costimulatory molecules frequently work as adaptors to recruit signaling molecules to the plasma membrane and hence amplify antigen-receptor-mediated signaling. Similarly, CD28 in T cells and CD19 in B cells both have cytoplasmic domains that can be tyrosine phosphorylated and thus can act as docking sites for SH2-domain-containing adaptors and enzymes.
The CD19 cytoplasmic tail contains nine tyrosine residues with the potential to be phosphorylated and interact with signaling molecules including lipid kinases, Vav-family GEFs, and adaptor proteins such as Grb2.
Other important examples of molecules that recruit key adaptor molecules to the plasma membrane are the lymphocytic activation molecule SLAM family of receptors and associated intracellular adaptors of the SLAM-associated protein SAP family Veillette The plethora of costimulatory molecules that can contribute to lymphocyte activation can be confusing, particularly because all seem to activate similar signal transduction pathways.
The key message is that these receptors function at different times and in different contexts. In contrast, BAFF is mainly produced by neutrophils, monocytes, and macrophages and hence allows crosstalk between B cells and these cells of the innate immune system. Moreover, cytokines have pleotropic roles.
Pdf to download. What is the role of T cells and antibodies in immunity? Like B cells, which produce antibodies, T cells are central players in the immune response to viral infection [ 1 ]. This causes the host cell to undergo programmed cell death, releasing molecules called damage-associated molecular patterns e. These molecules are recognized by macrophages and neighbouring endothelial and epithelial cells, causing them to produce pro-inflammatory cytokines, including chemokines Box 1 ; examples include. Monocytes, macrophages, and T cells are then recruited to the site of infection by these chemokines and other cytokines and promote further inflammation.
Naıve B cells are activated by antigen (Ag) in the presence of CD4 T-cell help. The activated B cells then continue down one of two divergent pathways.
In its lifetime a lymphocyte may or may not come into contact with the antigen it is capable of recognizing, but if it does it can be activated to multiply into a large number of identical cells, called a clone. Each member of the clone carries the same antigen receptor and hence has the same antigen specificity as the original lymphocyte. The process, called clonal selection , is one of the fundamental concepts of immunology.
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Figure 1.Annette B. 29.04.2021 at 04:21
T cells are generated in the T hymus and are programmed to be specific for one particular foreign particle antigen.Petruos B. 30.04.2021 at 07:02
B cells can be activated either by direct recognition of antigen by the B cell receptor or by the antigens presented on the T cells. Primary immune response is activated by the antigen recognition by the naïve B cells and their differentiation into antibody secreting plasma cells.Slimobmilneu 30.04.2021 at 09:37
A lymphocyte is a type of white blood cell in the immune system of jawed vertebrates.Cripenamcon 30.04.2021 at 19:51
The fate of T and B lymphocytes, the key cells that direct the adaptive immune response, is regulated by a diverse network of signal transduction pathways.