BISC 307L 1st Edition Lecture 32 Current Lecture Major Histocompatibility Complex o o All cells produce at least one of the MHC molecules o Each nucleated cell is labeled with a large complement of unique molecules o Non nucleated cells don t have MHC molecules red blood cells Only have 2 glycosurface proteins used for recognition called A and B Those that don t have either are O Classes of MHC Proteins o o Class 1 Expressed in all cells with nuclei Present antigens to T cells Cytotoxic T cells and helper T cells will recognize antigens by the antigens binding to the T cell receptors Has a lot of variability in the antigen binding site Alpha and beta chains T cell receptor binds to the antigen but T cell receptors don t bind to naked antigens like B cells The T cell receptor must also bind to the MHC class I presenting the antigen and must be stabilized by CD8 2 T cell receptors binding to two things presenting the antigen Antigen is presented by MHC class 1 like a sample of peptides being made inside the cell This is a strong binding and if a helper T cell agrees then it will activate the cytotoxic T cell and the cell will be killed by apoptosis o Class II MHC protein Expressed on the surface of dendritic cells macrophages and B cells Class II MHC also pick up samples of peptides in the cell that are part of the endocytotic process Phagocyte displays to lyphocytes a sample of antigens from things that have been phagocytized The helper T lyphocyte is receiving the signal This T cell receptor binds antigen and class II MHC receptor Has CD4 to stabilize the bonding Interleuken I cytokine helps stimulate the helper T cell Helper T cells mostly stay in the lymphoid tissues and the MHC cell comes to them Activation of B lymphocytes o o This on left is macrophage presenting fragment of antigen to class II MHC molecule and this activates the helper T cell Weak activation not fully activated unless B cell agrees o Triggers phagocytosis by the B cell the B cell presents those antigens to a helper T cell o Must be activated by phagocyte and B cell o 3 cells agreeing that something needs to be done results in active B lymphocyte and helper T cell o The helper T cell when activated is secreting cytokines to activate the B cell o The b Cell when fully activated will proliferate to form plasma cells and memory cells o Antibodies secreted IgM IgG o Antibodies secreted at a rate of 2000 second o There is a delay upon first exposure to antigen then there is a rise that lasts for several weeks o The large clone of memory B cells and memory helper T cells will persist and may live for the rest of your life and upon second exposure to the antigen are capable of a faster immune response Basis for vaccination o Probably don t even know you got sick the second time Activation of Cytotoxic T lymphocytes o o Activation of Cytotoxic T cells Active during responses to viral infection and cancer o Virus infected cell is displaying on its surface via class MHC I bearing antigen o This will activate Cytotoxic T cell but it is weak so needs agreement from helper T cell that there is a viral infection that needs to be attacked o Activated helper T cell secretes interleukin 2 and this is needed for the cytotoxic T cell to be fully activated proliferate into clonal and memory cells Clonal cells will kill the cell from within o The active cytotoxic t cell moves on and looks for more infected cells Chemical Communication Between Macrophages and T lymphocytes o o Cytokines are hormones endocrine and paracrine o This reemphasizes the chemical communication o The chemical communication is due to interleukin 1 acting as a paracrine hormone o The helper T cell secretes interleukin 2 and causes macrophage to secrete tumor necrosis factor and causes prevention of cancer o Cytotoxic t cells bring about their own destruction by once they are activated they start to express protein called FAS receptor These don t do anything until later when they express FAS ligand and this triggers apoptosis o Eliminates potential danger o This is exploited in compartments of the body that are immunologically privileged sites certain parts where cytotoxic T cells are not allowed Testesdeveloping sperm cells secrete protein that would cause apoptosis by cytotoxic T cells But sertoli cells secrete an FAS ligand and keep cytotoxic T cells out of the Testes Also anterior chamber of the eye Site where cytotoxic T cells aren t allowed Prevents clouding of the eye The epithelial cells that line this area also express FAS ligand and express molecules that suppress inflammation o One of the characteristics of some types of cancer is the expression of FAS ligand on the surface Will protect itself from cytotoxic killing Immunological Tolerance o o Why don t we die of autoimmune attack o Old idea during embryonic development T and B lymphocytes acquired receptors at random and could respond to anything that might be out there old view says that at some point late in fetal life T and B cells are tested by presenting antigens to them mostly class I and any T or B cell that responds to self antigens triggers apoptosis So left with T and B cells that don t respond to self cells o New idea found this isn t true Would expect to find T and B cells that don t respond to self antigens Found that actually most respond to self antigens Current view late in fetal development the cells are tested in bone marrow and thymus and there are 3 possibilities 1 Response will be strong vigorous response is killed by apoptosis clonal deletion 2 Weak response Also killed by apoptosis Makes sense because all kinds of mutations are allowed to accumulate and high rate of defective cell Any cell that isn t capable of responding is seen as defective 3 Moderate response Proven that functional But only responding moderately they ve proven that they are not that dangerous and can be controlled This is called positive selection these are the ones that stay 1 How do you test for reactions to cells that aren t in the thymus and bone marrow During this testing period the bone marrow expresses tissue from other organs liver or kidney 2 New T and B lymphocytes are actually produced throughout life and go through this screening not only in fetal life Do not stop at the end of fetal life example during pregnancy new huge thing growing inside of her and half of the genome is foreign Why isn t the fetus killed The mother s immune system is adapting and tolerates it Another example organ