Diagram showing the 2 Lineages of dendritic cells - Copyright Prof Dirk Werling DrMedVet PhD MRCVS There are two different lineages of dendritic cells: • From myeloid precursor cells • From plasmacytoid precursor cells Dendritic cells stimulate a primary T cell response; they migrate through tissues, track to T cell dependent areas of the and cluster with the T cells. Dendritic cells have unique capabilities to take up antigen by pathways involving phagocytosis, macropinocytosis and clathrin-coated pits.
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The cell-surface antigen phenotype distinguishes the dendritic cell from /macrophages and. Their main function is priming T helper cells. They produce cell signaling cytokine molecules known as.
Activation of T Cells: Helper and Cytotoxic After an antigen-presenting cell such as a macrophage has ingested and processed an antigen, it presents the antigen fragment, along with a class II marker protein, to a matching helper T cell with a T4 receptor. The binding prompts the macrophage to release interleukins that allow the T cell to mature. A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected (particularly with viruses),.
Maturation signals • Exogenous • Bacteria or their products (LPS, LTA, lipoproteins) • Viruses or their products (dsRNA, G-RSV) • Protozoa or their products • Helminths (SEA, ES 62) • Endogenous • Inflammatory mediators (IL-1/TNFα, hsp, FcR) • Immune cells (CD40L, CD47, FasL). Maturation of Dendritic Cells - Copyright Prof Dirk Werling DrMedVet PhD MRCVS Antigen Presentation Circulating differentiate to form immature dendritic cells called Langerhans Cells Langerhans cells sample the tissue fluid by endocytosis: • Foreign organisms are internalised • Within the dendritic cells, antigen is digested to peptides • Some of the peptides formed bind to the cell’s molecules The Langerhans cells leave the epithelium and travel via the afferent lymph flow. They are now known as Veiled Cells.
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Veiled cells enter the paracortical region of the where they present antigen to the T cells. They are now known as Interdigitating Dendritic Cells. T H1 cells boost macrophage response - B.
Catchpole, RVC 2008 TH 1 cells help macrophages digest bacteria - the organisms are contained in cellular vesicles. T H1 cells secrete a range of cytokines, including: • IL-2, which induces proliferation of both and. This stimulation of T cell proliferation is the main function of the T H1 cell. • Interferon gamma ( IFNγ) which activates tissue macrophages and is the principal effector mechanism in the defence against intracellular bacteria and parasites such as Mycobacteria, Brucella, Rickettsia Leishmania, Coccidia, and Babesia. IFNγ activates macrophages and stimulates them to produce enzymes triggering intracellular killing mechanisms - specifically: • Superoxide dismutase and myeloperoxidase that produce H 2O 2 and trigger the 'superoxide burst'.
• Nitric oxide synthase which produces nitric oxide. This is another example of the immune system working through the innate immune response, and this can even act to suppress antibody synthesis. T H2 cells incite increased antibody production - B. Catchpole, RVC 2008 T H2 cells help produce antibody where the organism is present in tissue fluid. The T H2 population influences B cell activation, proliferation and immunoglobulin production.
T H2 T cells also secrete a range of cytokines: • IL-4 which stimulates B cell growth and induces the heavy chain switch from to, and, as well as proliferation of basophils and mast cells. IL-4 can inhibit some T cell responses. • IL-5 which activates B cells and stimulates a high rate of proliferation. IL-5 also promotes immunoglobulin synthesis and the proliferation and differentiation of eosinophils. • IL-6 also activates B cells, stimulates a high rate of proliferation and promotes immunoglobulin synthesis. Common Functions of T H1 and T H2 Cells Both T H1 and T H2 cells produce IL-3 and granulocyte-macrophage colony stimulating factor (). These act to activate and induce proliferation of and.
Are the major phagocytic cells in the blood and the principal cells in acute inflammatory lesions whose function is chiefly the body's defence against extracellular bacteria. One of the major biological functions therefore of the activation of either T H subset is cytokine-controlled reactive.
T H17 Cells Still under investigation The T H17 cells form when T H0 cells are challenged with IL-6 and TGF-β to produce a number of cytokines that enhance the innate immune response. The produced enhance the extravasation and chemotaxis of to the site of infection, in the aim of combating extracellular bacteria. These cytokines include: • IL-17 • IL-17F • IL-6 • TNFα • IL-21 • IL-22 • IL-23 Importantly they do not produce: • IFNγ normally associated with T H1 cells • IL-4 normally associated with T H2 cells Cytotoxic T-Cells Cytotoxic T cells kill virus infected cells where the organisms are contained in the cell cytoplasm. Viruses are obligate intracellular pathogens that use the host cell machinery for pathogen protein synthesis; viral peptides associate with MHC class I and are expressed on the cell surface. Recognise the antigen-MHC complex. Cytotoxic T-cells secrete a pattern of cytokines similar to that of TH 1 cells: • IFNγ but not IL-2.
The IFNγ shifts the balance of the immune response in favour of TH 1 cells and there is therefore an increased level of T-cell proliferation. The initiation of the immune response via CTL leads to the selective proliferation of CTL which enhances the main mechanism of killing virally-infected cells. Killing Mechanism The CTl killing mechanism is initiated by direct CTL-target cell contact. • The cells involved bind by antigen/ class I-TcR interaction. This allows the CTL's intracellular granules to be localised at the area of contact - the granules contain most of the molecules responsible for cytotoxicity. • Direct cell contact stimulates the release of the granule contents into the area of contact between the two cells. The granules contain two groups of cytotoxic molecules.
• Perforin, which is structurally related to the component, C9 and forms pores in the cell membrane. • Granzymes, which are proteolytic enzymes that target cell nucleases and cause programmed cell death. T-Cell Activation T cells function only after recent activation by an antigen. • CD4 binds MHC class II - recognise antigen only in association with. • CD8 binds MHC class I - recognise antigen only in association with. Activation of T cells requires two distinct signals: • Signal 1 is the interaction of the TcR with the antigenic peptide/ complex on the antigen presenting cell.
• Signal 2 is the interaction of CD28 on the T cells with its ligand, CD80, on the antigen-presenting cell (APC). APC expression of CD80 only occurs after the engagement of pattern recognition on Fc receptors or activation by the cytokines Interferon, IL-1β or TNFα. Signal 2 only occurs after the recognition of DANGER. Activation Scenarios 1. No signal 1: T cell is not activated as there is no antigen.
Both signal 1 and signal 2 T cell is activated into clonal expansion and produces cytokines or becomes cytotoxic. Signal 1 but no signal 2 T-cell is triggered into apoptosis and dies. This is the basis of 'clonal deletion' and is a major mechanism of the development of tolerance. It ensures that T-cells do not react with self (non-dangerous) antigens. TCR Complex - Copyright Prof Dirk Werling DrMedVet PhD MRCVS The T cell Receptor, or TCR is always associated with CD3, forming what is referred to as the TCR complex.
TCR is expressed on the surface of T cells in a noncovalent association with a complex of transmembrane polypeptides. CD3 contains 3 distinct polypeptide chains that are expressed exclusively on T cells: γ, ε, and δ. These molecules are members of the Ig superfamily - the ε chain associates with both γ and δ - and they play a 'chaperone' role in transporting newly synthesized TCR molecules to the cell surface. CD3 also contains 2 identical chains: ζ and 16 kDa, which are found on T cells, macrophages and NK cells. Mice also can have an ε (eta) form. Response to Activation The response of the T cells to obtaining Signals 1 and 2 is to express the receptor for the cytokine interleukin-2 (IL-2) and CD4 + T-cells secrete IL-2.
The final trigger for clonal expansion is the engagement of IL-2R with IL-2 from any activated CD4 + T-cell. IL-2 produced by a CD4 + cell may also stimulate clonal expansion of the CD4 + cell. T-Helper Cell Function. TH1 and 2 selection is influenced by infection - B.
Catchpole, RVC 2008 The function of T helper cells is to regulate the immune response. The cytokines they secrete exert their influence on other cell populations; most of the different effector cells of the immune system are affected by one or more of the cytokines secreted by T H cells. TH cells secrete cytokines for only a short period after they have been activated; the range of cytokines that T H cells secrete after activation chiefly determines their function. Different T-helper cell subpopulations (T H1, T H2 and T H17 cells) secrete different sets of cytokines. References • Korn, T., Bettelli, E., Oukka, M. And Kuchroo, V.K.
(2009) IL-17 and Th17 Cells. Annual Reviews of Immunology 27: pp.485-517. Originally funded by the RVC Jim Bee Award 2007.
In fact, the 'T ' in T cell lymphocyte stands for thymus derived. T cell lymphocytes are necessary for cell mediated immunity, which is an immune response that involves the activation of immune cells to fight infection.
T cells function to actively destroy infected cells, as well as to signal other immune cells to participate in the immune response. T Cell Types T cells are one of three main types of lymphocytes. The other types include and natural killer cells. T cell lymphocytes are different from B cells and natural killer cells in that they have a called a T-cell receptor that populates their. T-cell receptors are capable of recognizing various types of specific antigens (substances that provoke an immune response).
Unlike B cells, T cells do not utilize to fight germs. There are several types of T cell lymphocytes, each with specific functions in the. Common T cell types include: • Cytotoxic T cells (also called CD8+ T cells) - are involved in the direct destruction of cells that have become cancerous or are infected with viruses.
Cytotoxic T cells contain granules (sacs containing digestive enzymes or other chemical substances) that they utilize to cause the target cell to burst open in a process called. These T cells are also the cause of transplant organ rejection. The T cells attack the foreign tissue as the transplant organ is identified as infected tissue. • Helper T cells (also called CD4+ T cells) - precipitate the production of antibodies by and also produce substances that activate cytotoxic T cells and white blood cells known as. CD4+ cells are targeted by HIV.
And destroys them by triggering signals that result in T cell death. • Regulatory T cells (also called suppressor T cells) - suppress the response of B cells and other T cells to antigens. This suppression is needed so that an immune response does not continue once it is no longer needed. Defects in regulatory T cells can lead to the development of an autoimmune disease. In this type of disease, immune cells attack the body's own.
• Natural Killer T (NKT) cells - have a similar name as a different type of lymphocyte called a natural killer cell. NKT cells are T cells and not natural killer cells.
NKT cells have properties of both T cells and natural killer cells. Like all T cells, NKT cells have T-cell receptors.
However, NKT cells also share several surface cell markers in common with natural killer cells. As such, NKT cells distinguish infected or cancerous cells from normal body and attack cells that do not contain molecular markers that identify them as.
One type of NKT cell known as an invariant natural killer T (iNKT) cell, protects the body against obesity by regulating inflammation in. • Memory T cells - help the immune system to recognize previously encountered antigens and respond to them more quickly and for a longer period of time.
Helper T cells and cytotoxic T cells can become memory T cells. Memory T cells are stored in the and and may provide lifetime protection against a specific antigen in some cases. T Cell Activation T cells are activated by signals from antigens they encounter. Antigen-presenting white blood cells, such as, engulf and digest antigens. Antigen-presenting cells capture molecular information about the antigen and attach it to a major histocompatibility complex (MHC) class II molecule. The MHC molecule is then transported to the and presented on the surface of the antigen-presenting cell. Any T cell that recognizes the specific antigen will bind to the antigen-presenting cell via its T-cell receptor.
Once the T-cell receptor binds to the MHC molecule, the antigen-presenting cell secretes cell signaling called cytokines. Cytokines signal the T cell to destroy the specific antigen, thus activating the T cell. The activated T cell multiplies and differentiates into helper T cells. Helper T cells initiate the production of cytotoxic T cells,, macrophages, and other to terminate the antigen.