Chapter 6: MHC Molecules and Antigen Presentation to T Lymphocytes (Part 1) Antigen Receptors TABLE 5-1: Features of Antigen Binding by the Antigen-Recognizing Molecules of the Immune System (From Abbas, Lichtman and Pillai, 8th Edition; p. 88) Feature Antigen-Binding Molecule Immunoglobulin (Ig) T cell receptor (TCR)* MHC molecules* Antigen-binding site Made up of three CDRs in VH and three CDRs in VL domains Made up of three CDRs in Vα and three CDRs in Vβ domains Peptide-binding cleft made of α1 and α2 domains (class I MHC) and α1 and β1 domains (class II MHC) Nature of antigen that may be bound Macromolecules (proteins, lipids, polysaccharides) and small chemicals Peptide-MHC complexes Peptides Nature of antigenic determinants recognized Linear and conformational determinants of various macromolecules and chemicals Linear determinants of peptides; only 2 or 3 amino acid residues of a peptide bound to an MHC molecule Linear determinants of peptides; only some amino acid residues of a peptide Affinity of antigen binding Kd 10−7–10−11 M; average affinity of Igs increases during immune response Kd 10−5–10−7 M Kd 10−6–10−9 M; extremely stable binding On-rate and off-rate Rapid on-rate, variable off-rate Slow on-rate, slow off-rate Slow on-rate, very slow off-rate CDR, complementarity-determining region; Kd, dissociation constant; MHC, major histocompatibility complex; (only class II molecules depicted); VH, variable domain of heavy chain Ig; VL, variable domain of light chain Ig. ∗ The structures and functions of MHC and TCR molecules are discussed in Chapters 6 and 7, respectively.Antigen Recognition Please recall, T cells are used to fight off intracellular infections, but they can also be used to activate other cells such as macrophages and B cells. Let’s take a look at how this is done. TABLE 6-1: Features of MHC-Dependent Antigen Recognition by T Lymphocytes (From Abbas, Lichtman and Pillai, 8th Edition; p. 108) Features of Antigens Recognized by T Cells Explanation Most T cells recognize peptides and no other molecules. Only peptides bind to MHC molecules. T cells recognize linear peptides and not conformational determinants of protein antigens. Linear peptides bind to clefts of MHC molecules, and protein conformation is lost during the generation of these peptides. T cells recognize cell-associated and not soluble antigens. Most T cell receptors recognize only peptide-MHC complexes, and MHC molecules are membrane proteins that display stably bound peptides on cell surfaces. CD4+ and CD8+ T cells preferentially recognize antigens sampled from the extracellular and cytosolic pools, respectively. Pathways of assembly of MHC molecules ensure that class II molecules display peptides that are derived from extracellular proteins and taken up into vesicles in APCs and that class I molecules present peptides from cytosolic proteins; CD4 and CD8 bind to nonpolymorphic regions of class II and class I MHC molecules, respectively.The MHC/TCR Interaction Two-Signal Hypothesis In order for a T cell to get activated, it needs 2 signals: Abbas, Lichtman and Pillai8_Figure 6-1; p.108 Abbas, Lichtman and Pillai8_Figure 4-18; p.83Functions of APCs The best way to activate a T cell is to use a DC (although, macrophages and B cells can also be used as an APC). Other APCs: Macrophages – B cells – Nucleated cells – Thymic epithelial cells – Abbas, Lichtman and Pillai8_Figure 6-2; p.109Abbas, Lichtman and Pillai8_Figure 6-4A; p.112 Dendritic Cells Please remember that antigen can enter from many different routes into the body. The skin is the largest organ and is the organ most commonly affected by infection. Additionally, the respiratory and digestive tracts are common routes for antigen entry (the genitourinary tract is another antigen entry route – anywhere there is an opening to the outside world). There are two categories of DC: Classical – Plasmacytoid – Tissue Resident Dendritic Cells and Activated Dendritic Cells DC are great cells to use to stimulate a T cell response because: - - - -Abbas, Lichtman and Pillai8_Figure 6-5; p.113Chapter 6: MHC Molecules and Antigen Presentation to T Lymphocytes (Part 2) The Major Histocompatibility Complex (MHC) First discovered from transplant studies (transplantation among non-identical individuals resulted in rejected tissue whereas transplanted tissue from genetically identical individuals were accepted). Years later they were identified to play a major role in the immune response to protein antigens. MHC Restriction Abbas, Lichtman and Pillai8_Figure 6-6; p.116The MHC Loci Mouse and human MHC loci are similar in structure and organization and are the most polymorphic (most variable) genes in the genome! There are three MHC I genes: HLA-A, HLA-B, HLA-C There are three MHC II genes: HLA-DP, HLA-DQ, HLA-DR In addition to being useful in transplantation, MHC molecules are also used to present antigen peptides to T cells. Let’s take a closer look… MHC I and MHC II Molecules Abbas, Lichtman and Pillai8_Figure 6-7; p.117 Abbas, Lichtman and Pillai8_Figure 6-10; p.120 (on left) and Figure 6-12; p.121 (on right). Courtesy of Dr. P. Bjorkman, California Institute of Technology, Pasadena.Rules of pairing polypeptide chains to make an MHC II molecule: • • TABLE 6-5 Comparative Features of Class I and Class II MHC Pathways of Antigen Processing and Presentation (From Abbas, Lichtman and Pillai, 8th Edition; p. 125) Feature Class I MHC Pathway Class II MHC Pathway Composition of stable peptide-MHC complex Polymorphic α chain, β2-microglobulin, peptide Polymorphic α and β chains, peptide Types of APCs All nucleated cells Dendritic cells, mononuclear phagocytes, B lymphocytes; endothelial cells, thymic epithelium Responsive T cells CD8+ T cells CD4+ T cells Source of protein antigens Mainly cytosolic proteins (usually synthesized in the cell; may enter cytosol from phagosomes); also nuclear and membrane proteins Endosomal and lysosomal proteins (mostly internalized from extracellular environment) Enzymes responsible for peptide loading of MHC Proteasomes Endosomal and lysosomal proteases (e.g., cathepsins) Site of peptide loading of MHC Endoplasmic reticulum Specialized vesicular compartment Molecules involved in transport of peptides and loading of MHC molecules Chaperones, TAP in ER Chaperones in ER; invariant chain in ER,