Lecture 8: Antigen Presentation to T Lymphocytes 10/01/2024 PDF

Lecture 8 Antigen Presentation to T Lymphocytes 10/01/2024 Learning Objectives Recognition of The generation of ab T- The MHC and its function nonpeptide ligands by cell receptor...

Lecture 8 Antigen Presentation to T Lymphocytes 10/01/2024 Learning Objectives Recognition of The generation of ab T- The MHC and its function nonpeptide ligands by cell receptor ligands unconventional T-cell subsets  The generation of ab T-cell Antigen presentation receptor ligands Antigen processing Antigen Presentation To initiate immune responses, antigens are captured from their side of entry and concentrated in secondary (peripheral) lymphoid organs through which naive T cells circulate constantly, T cells recognize and respond to cell-associated antigens and not to soluble, cell-free antigens. The task of displaying host cell-associated antigens for recognition by CD4+ and CD8+ T cells is performed by specialized proteins called MHC. MHC molecules display antigens from different cellular compartments to different classes of T cells. Properties of antigens recognized by T cells: 1. Most T cells recognize only short peptides. 2. Receptors for CD4+ and CD8+ T cells are specific for peptide antigens that are displayed by MHC molecules – MHC Restriction Antigen Processing – various cellular compartments from which antigen can be derived Antigen processing: the generation of peptides from native proteins There are two categories of major intracellular compartments, separated by membranes 1. Cytosol 2. Vesicular compartments – involved in endocytosis and secretion Peptides derived from cytosol – transported into ER – loaded on MHC I Virus and certain bacteria Direct presentation Both somatic and immune cells Fig 6.1 Cells become targets of T-cell recognition by acquiring antigens from either the cytosolic or the vesicular compartments Receptor-mediated endocytosis Direct presentation Fig 6.2 Somatic and immune cells Immune cells Cross-Presentation of Antigen The ability of certain APCs (mostly DCs) to take up, process and present antigens from exogenous sources with MHC I to CD8 T cells e.g. a virus that affects only epithelial cells The activation of naïve CD8 T-cells into activated CD8 T-cells by this pathway is called cross-priming Important in immunity against tumors Fig 6.3 Autophagy Pathway For the delivery of cytosolic antigens for presentation by MHC II Self-cytosolic proteins for the induction of tolerance to self antigens Cytoplasmic proteins are delivered into the endocytic system (autophagosomes) for degradation in lysosomes Fig 6.4 Protein Degradation in the Cytosol Carried out by a large, multi-catalytic protease complex k/as the proteasome – the set of cytosolic proteases responsible for generating the majority of MHC-I-presented peptides 20S catalytic core and two 19S regulatory caps, one at each end One of the 19S caps binds and delivers proteins into the proteasome, while the other keeps them from exiting prematurely Proteins in the cytosol are tagged for degradation via the ubiquitin- proteasome system Fig 6.5 The Ubiquitin-Proteasome System Begins with the attachment of a chain of several ubiquitin molecules to the target protein – ubiquitination First, a lysine residue on the targeted protein is chemically linked to the glycine at the carboxyl end of one ubiquitin molecule Ubiquitin chains are then formed by linking the lysine at residue 48 (K48) of the first ubiquitin to the carboxyl end of a second ubiquitin until at least four ubiquitin molecules are bound K48-linked ubiquitin chain recognized by 19S cap – unfolded – introduced into the proteasome catalytic core – protein chopped up into short peptides – released into cytosol Fig 6.5 TAP-1 and TAP-2 form a peptide transporter in the ER membrane Peptides from the cytosol are transported by TAP (Transporters associated with antigen processing)-1 and -2 into the endoplasmic reticulum before binding to MHC I The carboxyl terminus of peptide antigens appears to be produced by cleavage in the proteasome. However, the amino terminus of peptides that are too long to bind MHC class I can be trimmed by an enzyme called the endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP), also called ERAP1, and in humans by a second enzyme, ERAP2. Like other components of the antigen-processing pathway, expression of ERAP1 is increased by IFN-γ stimulation Mechanism of Peptide Processing and Loading on MHC Class I Molecules Fig. 6.8 Peptide loading complex (PLC): calreticulin, tapasin, ERp57, and TAP Peptides that Bind to MHC Class II Molecules are Generated in Acidified Endocytic Vesicles Example of proteases: cathepsin B Fig 6.10 The Invariant Chain directs Newly Synthesized MHC Class II Molecules to Acidified Intracellular Vesicles Fig 6.11 CLIP: Class II-associated invariant chain peptide HLA-DM facilitates the loading of antigenic peptides onto MHC class II molecules Fig. 6.13 Mechanism of Peptide Processing and Loading on MHC Class II Molecules Cathepsin S Image credit: Immunology by S. Juris. Oxford Press Recap The ligand recognized by the TCR is a peptide bound to an MHC molecule MHC I and II acquire peptides at different intracellular sites and activate CD8 and CD4 T-cells, respectively MHC Class I molecules are synthesized in the ER and acquire peptides from cytosolic protein degradation via proteasomes, with TAP assisting in peptide transport. DCs can perform cross-presentation, loading exogenous protein-derived peptides onto MHC Class I, allowing CD8 T cell activation against pathogens that may not infect DCs. MHC Class II molecules don't acquire peptides in the ER; instead, the invariant chain inserts CLIP, followed by cleavage in acidic endosomes. CD4 T cells recognizing peptide: MHC Class II complexes have diverse roles, including activating macrophages, aiding B cell antibody production, and regulating immune responses. MHC Diversity and Peptide The MHC and Presentation to T Cells its function The function of MHC molecules is to bind peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate T cells Consequences are almost always deleterious: o Virus-infected cells are killed o Macrophages are activated to kill bacteria living in their vesicles o B cells are activated to make Igs to eliminate or neutralize pathogens Why is a pathogen unsuccessful at evading MHC-mediated immune responses? MHC Diversity and Antigen Binding The MHC gene family is divided into three subgroups – class I, class II, and class III Diversity of antigen presentation, mediated by MHC classes I and II, is attained in multiple ways: 1. The MHC’s genetic encoding is polygenic, 2. MHC genes are highly polymorphic and have many variants, 3. Several MHC genes are expressed from both inherited alleles (variants) – codominance Key terms: Allele: one of a number of alternative forms of the same gene occupying a given position on a chromosome Polygenic: having an infinite number of derivatives at a point Haplotype: all the alleles of every MHC class I and II genes in an individual MHC Diversity – Driven by Genes MHC is polygenic: it contains several MHC class I and MHC class II genes, so that every individual possesses a set of MHC molecules with different range of peptide-binding specificities At least 3 different MHC class Ia molecules At least 3 different MHC class II molecules Ch 6 Ch 17 Fig 6.16 The Protein Products of MHC Class I and Class II Genes are Highly Polymorphic Take-home message: MHC genes are both highly polymorphic and tightly linked, so a set of alleles is inherited as one unit, from each parent, known as a haplotype. The evolution of MHC polymorphism ensures that a population will not succumb to a new pathogen or a mutaed one, because at least some individuals will be able to develop an adequate immune response to won over the pathogen MHC Polymorphism Affects Antigen Recognition by T Cells by influencing both Peptide Binding and the Contacts between the TCR and MHC Molecule Three properties are affected by MHC polymorphism: 1. The range of peptide bound, 2. the conformation of the bound peptide and 3. The direct interaction of the MHC molecule with with the TCR Fig 6.21 T-cell Recognition of Antigens is MHC Restricted Fig 6.23 Non-Peptide Antigen Presentation Nonpeptide ligands Non-peptide antigens E.g: Small lipid containing antigens, small molecules, metabolites Specialized MHC class I molecules act as ligands for the activation and inhibition of NK cells and unconventional T-cell subsets. Presented by structurally similar proteins encoded outside the MHC locus o non-classical class I molecules o CD1 family of proteins o MR1: MHC class I-related protein Checkpoint questions for Lecture 8 1. Explain the process of antigen presentation by MHC class I and II pathways 2. What is the role of cross-presentation in DCs? 3. Define promiscuous binding site as it relates to MHC molecules and the role if anchor residues in peptide binding to MHC molecules 4. Give an example of non-peptide antigen presentation Assigned Readings Chapter 6 6-1, 6-2, 6-3, 6-4, 6-6, 6-7, 6-8 InQuiziitve 20241001 Readings Due Oct 8, noon