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20 Cards in this Set
- Front
- Back
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What does CD4+ helper T cell do? |
Influences B-cell development via cytokines that help B-cells to make antibody in response to antigen exposure. |
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What does CD8+ helper T cell do? |
They are cytotoxic and kill other cells. There are twice as many CD4+ cells present in blood than CD8+ cells. Together they account for 85% of lymphocytes |
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What are plasma cells? |
Main antibody producing cells of the body. > Memory B-cells are long-lived and circulate as quiescent cells, not producing antibodies. However they can rapidly produce antibodies the next time they encounter the same antigen. |
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Clonal selection hypothesis - adaptive immunity |
Each naive lymphocyte entering the blood stream carries receptors of a single specificity, that recognises only one antigen. > during development, a unique genetic mechanism (genetic recombination) operates to generate hundreds of different variants of the antigen receptor molecules on the lymphocyte surface. THEREFORE, although each lymphocyte carries receptors of one specificity, each lymphocyte carries many copies of its unique receptor and the specificity of each lymphocyte is different. 1. A single progenitor cell gives rise to a large number of lymphocytes, each with a different specificity 2. Potentially self-reactive immature lymphocytes are removed before they can mature (clonal deletion). This occurs by apoptosis of T-cells in the thymus 3. Mature, naive cells recognise and bind specific foreign antigen 4. Resulting in proliferation and differentiating into a clone of effector cells that can dispose of the antigen |
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How is the diversity of lymphocyte antigen receptors generated? |
Lymphocyte antigen receptors are inherited as sets of gene segments, each gene segment encoding a different part of the receptor. The gene segments are joined together randomly to form a stretch of DNA that codes for an entire receptor. Since there are many different segments in each set, and different segments join up randomly in different cells, each cell generates a unique code for the antigen receptor. > gene rearrangement > the same basic mechanism to generate diversity in TCR and B-cells |
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Structure of a T-cell receptor (TCR) |
It is a heterodimer of two different glycoprotein chains; alpha and beta. > the external part of each chain consists of two regions; the variable domain and the constant domain. The hinge region attaches the molecule to the cell membrane. Each T-cell has around 30,000 receptors, and all recognise only one antigen |
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Structure of a T-cell receptor (TCR) |
It is a heterodimer of two different glycoprotein chains; alpha and beta. > the external part of each chain consists of two regions; the variable domain and the constant domain. The hinge region attaches the molecule to the cell membrane. Each T-cell has around 30,000 receptors, and all recognise only one antigen |
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How does diversity in TCR function arise? |
The antigen-recognition site on the molecule is made up of the variable domain of both alpha and beta chains. However, the variable region is coded by three discrete gene segments (variable genes, diversity genes + joining genes). For each of these gene segments, there are a number of different copies of the gene sequence (see table). > gene sequences can rearrange randomly and recombine during development to give rise to thousands of different TCRs. > the variable region is coded for by the combination of the VDJ gene sequences, which then combine with a constant region sequence to give VDJC sequence for the whole chain. • no. Possible alpha chains = 75 x 60 x 1 = 4,500 • no. Possible beta chains = 50 x 2 x 13 x 2 = 2,600 > then 2,600 x 4,500 = 11.7 x10^6 is the number of different TCR antigen recognition sites |
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Why is gene rearrangement important? |
> enables a limited number of gene segments to generate a very diverse set of proteins > as each cell assembles a different set of gene segments to code for its antigen receptor, each cell expresses a unique receptor > irreversible change of a cell's DNA therefore all daughters of that cell will inherit genes coding for the same receptor (clone) |
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Lymphocytes circulate between blood and lymph |
T-cells and B-cells are produced in the primary lymphoid organs, the thymus and bone marrow. Naive lymphocytes must circulate through secondary or peripheral lymphoid tissue (lymph nodes) in order to encounter foreign proteins for the first time and become activated. > continuous recirculation through the lymph nodes ensures that rare antigen-specific lymphocytes encounter their specific antigen - circulate between the blood and the lymph and back to the blood > drainage of lymph fluid from sites of infection to the lymph nodes is important in carrying the pathogen either directly or enclosed in phagocytic cells to the lymph nodes. > if infection is established, large amounts of antigen is taken up by the phagocytes; but free antigens in the lymph fluid must be trapped by antigen-presenting cells in the lymph node. Here they present the antigens to specific naive cells which become activated and proliferate. • proliferation of lymphocytes in lymph nodes during and infection results in swollen glands |
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Antigen presentation |
T-cells are 'blind' to free antigen and are only activated by antigens that are presented to them by professional antigen-presenting cells (APC). These cells accumulate in peripheral lymphoid tissue. > APC in the lymph nodes capture antigens from lymph fluid and APC in the spleen capture antigens from blood There are three professional antigen presenting cells; 1. Macrophage - expression of MHC is increased following ingestion of pathogen. Bacteria degraded by lysosomes generate peptides that can be presented by MHC molecules on the surface of the macrophage to the TCR on naive T-cells 2. Dendritic cell - specialised to trap antigens in tissue (lung and skin) and migrate to the lymph nodes to present antigens to T-cells (only function!). Highly efficient and potent inducer of T-cell activation. They have high levels of MHC molecules and re specialised to cope with viral infection 3. B-lymphocyte - present antigen to activated T-cells that recognise same foreign protein. Resulting in the antibody response |
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MHC molecules on APC |
T-cells are specialised to recognise foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex (MHC) > MHC genes produce two classes of MHC molecule, MHC-I and MHC-II, which differ in subtle ways but share major structural features. > most important structural feature is the cleft in the extracellular portion of the molecule. During synthesis of the MHC protein inside a cell, his cleft traps peptide fragments and carries them to the cell surface. > CD4+ helper T cells - dendritic cells are infected by a wide range of viruses and present viral peptides on either MHC-I to naive CD8 T-cells or MHC-II to naive CD4 T-cells |
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MHC molecules on APC |
T-cells are specialised to recognise foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex (MHC) > MHC genes produce two classes of MHC molecule, MHC-I and MHC-II, which differ in subtle ways but share major structural features. > most important structural feature is the cleft in the extracellular portion of the molecule. During synthesis of the MHC protein inside a cell, his cleft traps peptide fragments and carries them to the cell surface. > CD4+ helper T cells - dendritic cells are infected by a wide range of viruses and present viral peptides on either MHC-I to naive CD8 T-cells or MHC-II to naive CD4 T-cells |
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MHC-I |
Collect fragments of viral proteins which are made in the cytoplasm and display them on the cell surface. > made by all cells of the body (except RBC). > MHC class-I protein is coded by three polymorphic genes called HLA-A, HLA-B and HLA-C. One gene is inherited from each parent and equally expressed so cells can express 6 different class-I molecules |
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MHC-II |
Bind peptides derived from proteins in intracellular vesicles (such as those from phagocytosis or cell surface immunoglobulins on B-cells). > macrophages, dendritic cells and B-cells > neutrophils are NOT antigen presenting cells > three sets of polymorphic MHC-II genes; HLA-DR, HLA-DQ, HLA-DP > MHC-II made up of two chains; since the alpha chain of one allele may associate with the beta chain of the other allele, a number of class-II variants can arise • MHC-II recognised by CD4+ helper T cells |
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Antigen presentation and co-stimulation activates T-cells |
The first encounter of a naive T-cell with antigen on an APC in the lymph node stimulates the primary immune response, and also generates immunological memory which provides faster and more efficient protection against a pathogen the next time. The MHC molecules promote the interaction between APC and naive T cells. > MHC-II present bacterial peptides to specific T-cell receptors on naive CD4+ T cells. CD4 is a co-receptor for the TCR and interacts only with self-MHC-II. > MHC-I molecules present viral peptides to TCR on naive CD8+ cells. CD8 is a co-receptor for TCR on cytotoxic T-cells and interacts only with self-MHC class-I. • Binding of antigen to the specific TCR primes the cell for activation and co-stimulatory activity. Molecules which are only present on APC, bind to receptors on T-cells and stimulate the synthesis of IL-2 and the IL-2 receptor on the T-cell surface. • when IL-2 binds to its receptor T-cells proliferate with one cell producing thousands of daughters each with the same TCR. • T-cells also differentiate over 4-5 days, into armed effector T-cells which have the capacity to synthesise all of the proteins required for their specialised function as helper T-cells or cytotoxic T-cells > effector cells then act immediately, leaving the lymph node to find site of infection |
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Explain co-stimulation process |
T-cell needs to be 'told' that the TCR has bound its antigen/MHC ligand complex. This signalling function is carried out by invariant proteins of the CD3 complex (CD3 gamma, delta, greek E) and the greek z protein that are associated with the TCR on the cell surface. > All T-cells are CD3+. The cytoplasmic domains of all these proteins associate with protein tyrosine kinases in the cytoplasm to initiate a cascade of intracellular signalling pathways following the binding of the antigen/MHC complex. • During antigen recognition, CD4 and CD8 associate with the TCR on the T-cell surface and are known as co-receptors. The cytoplasmic tails of CD4 and CD8 associate with tyrosine kinases and contribute to cell signalling. The binding of the complex to its antigen-specific TCR and either CD4 or CD8 triggers the cell but still requires a co-stimulatory signal in order for the T-cells to proliferate and differentiate into armed T cells. > the best co-stimulatory molecules are the B7-glycoproteins that bind and activate CD28 on T-cells to provide the second activation signal leading to IL-2 and IL-receptor synthesis and T cell proliferation. 😢 without co-stimulation presentation to T cells, they are anergic and unresponsive. |
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What happens after T cell activation? |
Resting APC express few or no B7 co-stimulatory molecules and fail to activate naive T-cells. TCR dependent recognition of antigen alone is not enough to stimulate T cell proliferation. > cytokines produced in response to microbes activate APCs and stimulate the expression of B7 co-stimulator molecules. > B7-CD28 interactions stimulate the expansion and differentiation of naive T cells through increasing IL-2 and IL-2 receptor expression on T cells. CTLA-4 is a high affinity (higher than CD28) receptor for B7 and expression of CTLA-4 is upregulated on activated T cells. > T cell responses are terminated by T cell CTLA-4 interaction with B7 on APCs; feedback inhibition. |
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What are the three most important functions of macrophages? |
1. Phagocytosis of opsonised bacteria at sites of infection 2. Regulation of neutrophil recruitment to sites of infection by cytokine synthesis 3. Presentation of foreign antigens to naive T-cells in the lymph nodes |
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What are the three most important functions of activated T cells? |
1. Activation of macrophages by CD4+ helper T cells (Th1 cells) 2. Activation of B-cells by CD4+ helper T cells (Th2 cells) to generate antibody response 3. Killing of virus infected cells by CD8+ cytotoxic T-cells |
