BISC 307L 2nd Edition Lecture 33 Current Lecture Major 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 Proteins Class I expressed in all cells w nuclei Works by presenting antigens to T cells There are two important types of T cells cytotoxic and helper They will recognize antigens by virtue of the fact that antigens will bind to T cell receptors which have a different structure than the B cell receptor But they are similar in that they have a lot of variability in the antigen b inding site Variability arises by gene recombination as it does for the Blymph receptors But this is a dimer not a tetramer and it is a heterodimer with an alpha chain and beta chain And a given T cell during its differentiation will commit itself by gene rearrangement to producing only one type of alpha chain and one type of beta chain that will combine to produce a receptor with one type of antigen binding specificity The T cell receptor binds to the antigen so here is a cytotoxic T cell receptor in purple binding to an 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 T cell 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 T cell 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 specific defenses 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 addition to 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 MHC molecule presenting that antigen then that will potentially activate the cell It needs more to be fully 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 contact with 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 Lymphocytes On 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 phagocytosis by the B cell And the B cell takes antigenic fragments from the bacterium and presents those antigens to a