Lecture 3: MHC and HLA 1. Professional antigen presenting cells present antigen to CD4+ T cells. a.

These cells are dendritic cells, macrophages, and B cells. i. Major Histocompatibility Complex (MHC) codes for these cells. 1. Class I MHC is found in all cells, including professional antigen presenting cells. a. Encoded by three loci (A, B, and C). i. Codominately expressed b. Composed of a transmembrane polymorphic peptide chain in association with a smaller polypeptide, Beta 2-microglobulin. 2. Class II MHC is found only in professional Antigen presenting cells. a. Encoded by the D locus (DP, DQ, DR). b. Heterodimer of two transmembrane polymorphic polypeptide chains. c. During processing, which we will cover later, an invariant chain is present to prevent binding to other molecules. 2. Cells that present antigen to CD8 T cells are not called antigen-presenting cells, rather they are called Target cells because presentation to CD8 T cells targets them for destruction. Remember antigen-presenting cells are intermediates, not targets. 3. Dendritic cells a. Most efficient presenter of antigen during a primary immune response. This is because they are present in all lymphoid and nonlymphoid tissues (except the brain). b. Dendritic cells function as sentinels, guarding against invaders. i. If they encounter them they take them to secondary lymphoid organs. c. In the skin dendritic cells are called Langerhan cells. 4. Macrophages a. Not as effective as Dendritic cells because they are only present at the site of infection and not throughout the body like dendritic cells. Dendritic cells are more mobile, they can capture an invader and bring them places where macrophages stay in the site of infection. 5. B-cells a. Recognize antigen via antigen specific receptors. Because this is so specific B-cells can bind even at very low antigen concentrations. 6. Polymorphism a. Class I and Class II MHC molecules are said to be polymorphic. This means that they are found in multiple forms throughout the population. b. You get three copies from each parent.

i. This is advantageous because otherwise there may be a whole in our protection and a antigen would form that we could not defend against. 7. Class II MHC restriction a. Class II MHC molecules can only present to CD4+ T cells and CD4+ T cells can only see antigen presented by Class II MHC molecules. b. Class I MHC restriction is the same concept. Class I MHC cells present only to CD8 T cells and CD8 T cells can only see antigen through Class I MHC cells. 8. Exogenous Antigen processing and presentation by Class II MHC a. An antigen is present extracellularly, its brought in via endocytosis. b. Endosome fuses with a lysosome that releases its contents inside. i. The contents dissolve the antigen c. Another vesicle fuses with the endolysosome that contains Class II MHC receptors. The acidic environment dissolves the invariant chain allowing the receptors to take up the antigen fragments. i. Remember the invariant chain was covering the Class II MHC receptor site preventing it from binding to other molecules. d. These receptors are then taken to the cell surface . 9. Endogenous Antigen processing and presentation by Class I MHC a. Antigen is present in the cytoplasm of the cell. b. Ubiquitin attaches to the antigen targeting it for destruction. c. The proteasome degrades the antigen to peptides. d. TAP (Transporter of Antigen Processing) picks up the peptides and transports them to the endoplasmic reticulum. e. The peptide fragments join the Class I MHC molecules and are released to fuse with the cell membrane. 10. Cross Presentation a. In some cases exogenous antigen is presented to Class I MHC molecules. b. Some hypothesize that this could be because molecules escape from the endosome. 11. Some molecules are able to escape this processing. a. Herpes Simplex Virus (HHV-1,2) i. Inhibits TAP, therefore Class I MHC complexes do not form and care not presented on the cell surface. b. Epstein Barr Virus (HHV-4) i. Inhibits the activity of proteasomes preventing the hydrolysis of viral proteins into peptide size fragments. In this way the TAP cannot pick them up due to their size. c. Cytomegalovirus (HHV-5) i. Hinders the expression of Class I MHC by directing the vesicles containing the receptor/antigen into the cytoplasm where it is degraded.