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USC BISC 307L - Mechanisms of Acquired Immunity Part II
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BISC 307L 2nd Edition Lecture 33 Current LectureMajor Histocompatability Complex (MHC)Recap: All cells produce at least one of the types of MHC molecules. There are several dozen proteins – hundreds of different alleles on the population, people are heterozygous for – that means each nucleated cell is labeled with a large complement of unique cell surface glycoproteins. Nonnucleated cells don’t have this, for example, RBC’s don’t have MHC molecules. They only have two/three cell surface glycoproteins that they use for recognition, and they are called A and B. There are four blood types, so crossmatching blood or tissue matching blood for transfusions, and blood is a fluid tissue so it is a tissue transplant, is one thing that MHC molecules do. Another thing they do is present antigens to lymphocytes. Classes of MHC ProteinsClass I – expressed in all cells w/nuclei.Works by presenting antigens to Tcells. There are two important types ofT cells – cytotoxic and helper. They willrecognize antigens by virtue of the factthat antigens will bind to T-cellreceptors, which have a differentstructure than the B cell receptor. Butthey are similar in that they have a lotof variability in the antigen b indingsite. Variability arises by generecombination, as it does for the B-lymph receptors. But this is a dimer,not a tetramer, and it is a heterodimerwith an alpha chain and beta chain. And a given T cell during itsdifferentiation will commit itself by gene rearrangement to producingonly one type of alpha chain and one type of beta chain that willcombine to produce a receptor with one type of antigen bindingspecificity.The T cell receptor binds to the antigen, so here is a cytotoxic T cell receptor in purple binding toan antigen (the blue triangle) but T cell receptors do not bind to naked antigens like B cell receptors do. The antigen has to be part of a multidimensional binding event, that is, the T cell receptor has to bind the antigen but also the class I MHC presenting the antigen. And this complex between the antigen, the MHC molecule, and the receptor, has to be stabilized by binding of a cytotoxic Tcell binding protein called CD8, a specific protein for a specific marker of cytotoxic T cells. So there are two t-cell receptors binding to two things being presented by the antigen presenting cell. And all of this multiple binding has to happen in order for the T cell to be activated. The antigen is presented by the cell, and this is a class I MHC so every cell in your body except RBC’s produces this. And when the MHC class I molecule is made inside the cell, it picks up peptide fragments being synthesized in the cell and carries them and displays them on the surface. So the message displayed by every cell in your body except RBC’s is to present to cytotoxic T cells a sample of the peptides being made inside the cell. If the cytotoxic T cell binds recognizes the antigen being presented, and if a helper T cell agrees, then that will fully activate the cytotoxic Tcell and its response will be to kill the cell.On the right side is a class II MHC protein, and class II MHC proteins are expressed on the surface of three types of phagocytic cells: dendritic cells, macrophages, and B lymphocytes. Dendritic cells and macrophages are active phagocytes – B cells also phagocytize antigens but the function of that is not necessarily to kill the thing bearing the antigen but to activate specificdefenses. Class II MHC proteins also pick up peptide fragments in the cell, but in different compartments within the cell. Peptide fragments that are part of the endocytic degradation pathway such as when things get phagocytized and go into vesicles. They get degraded, and those degraded peptides get picked up by class II molecules and are presented on the surface. So these phagocytes are displaying to lymphocytes a sample of the things it has phagocytized, in additionto whatever its class I MHC proteins are showing (not illustrated here).The cell receiving the signal is the helper T lymphocyte. Helper T lymphocyte has a helper T receptor like a cytotoxic T cell, but this one is different – it has an antigen binding site like the cytotoxic T cell receptor, but what makes this a Helper T cell receptor is that this T cell receptor needs to bind the antigen and it needs to bind a class II MHC molecule, not a class I. Does not bind to antigens presented by class I. And it has a specific membrane protein called CD4. If this helper T cell’s two receptors, CD4 and its T cell receptor bind to the antigen and the class II MHCmolecule presenting that antigen, then that will potentially activate the cell. It needs more to befully activated though. Part of what it gets is a cytokine called Interleukin 1 secreted by the phagocyte when the phagocyte binds to a helper T cell, which will stimulate the helper T cell.Geographical Problem – Lymphocytes are mainly in lymphoid tissue, if cytotoxic T cells are patrolling all tissues in the body and helper T cells are going to be alert to infections and other threats anywhere in the body, how do the lymphocytes get there? How do they come in contactwith each other? In the case of the class I MHC proteins, the cytotoxic t cells are mainly on patrol – they leave the lymphoid and cruise through every tissue in the body and eventually will contact every cell in the body to sample it and conduct surveillance and make sure nothing inappropriate is going on. So the cytotoxic T cells go out and look for problems. Helper T cells mainly stay in lymphoid tissues and the antigen presenting cells come to them. Macrophages play an important role in this because they are highly motile. Dendritic cells aren’t, they are fixed. But once a macrophage ingests a bacteria, the macrophage will leave the area of infection, find a lymph capillary, enter it, and follow the lymphatic fluid to a lymph node or other lymphoid tissue and look for helper T cells that can react. Activation of B LymphocytesOn the left (figure on page below) is what we saw before – a macrophage presenting an antigen fragment to a helper T cell by means of the class II MHC. And this is going to activate the helper T cell. But this is a weak activation. Helper T cell won’t be fully activated unless a B cell agrees. So the macrophage has ingested the bacterium, and at the same time, the B cell has also bound that specific type of bacterium. That binding there activates the B cell weakly and also triggers


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