Antigen Presentation to T Lymphocytes PDF

Antigen Presentation to T Lymphocytes Literature: Chapter 6, Janeway’s Immunobiology ETH Zurich Lecture on “Pharmaceutical Immunology I” Prof. Dr. Cornelia Halin Winter 535-0830-00L HS 2024 ...

Antigen Presentation to T Lymphocytes Literature: Chapter 6, Janeway’s Immunobiology ETH Zurich Lecture on “Pharmaceutical Immunology I” Prof. Dr. Cornelia Halin Winter 535-0830-00L HS 2024  Revision from Chapter 1 α:β T-cells recognize antigen-derived peptides presented on MHC molecules MHC class I : expressed by virtually all cells in the body recognized by cytotoxic CD8+ T cells present fragments of proteins expressed by the cell itself (i.e. derived from cytosol) MHC class II: expressed by antigen-presenting cells (DCs, macrophages, B cells) present fragment of proteins that were taken up into from the outside (e.g. by phagocytosis) recognized by CD4+ T cells In this Chapter we will study in detail how antigen is presented to T cells on MHC molecules Content 1. The generation of α:β T-cell receptor ligands 2. The major histocompatibility complex and its function 3. Generation of ligands for unconventional T-cell subsets (not part of exam) 3  1. The generation of α:β T-cell receptor ligands 1. The generation of α:β T-cell receptor ligands The cytosol and the vesicular system are main two intracellular compartments which antigens can be derived Peptides derived from the cytosol are transported into the endoplasmic reticulum and directly loaded onto newly synthesized MHC class I molecules. Extracellular antigen is taken up by endocytosis or phagocytosis into endosomes or phagosomes. These then fuse with the lysosome, where loading onto MHC class II molecules.  1. The generation of α:β T-cell receptor ligands Depending on the compartment where they were encountered in pathogen-derived antigens are presented on either MHCI or MHCII Presentation by MHC class I 1. The generation of α:β T-cell receptor ligands Peptides are generated from ubiquitinated proteins in the cytosol by the proteasome 20S core: Proteasome: Complex of 28 subunits, arranged in four stacked around rings degradation of damaged a hollow core. Twoand inner rings unneeded proteins contain the proteolytic subunits (β1, β2, and β5). 19S regulator: forms a channel composed of a A basecore and regulatory containing units form a regulatory nine subunits cap on both ends of the 20S core channel. Immuneproteasome: Upon stimulation with interferons (e.g. produced during a viral infection), the catalytic subunits in the “constitutive” proteasome get exchanged. This alters the enzymatic specificity, yielding more peptides with suitable anchoring residues for presentation on MHC molecules. Also MHC molecules are induced by interferons => more antigen presentation. Presentation by MHC class I 1. The generation of α:β T-cell receptor ligands TAP transports peptides produced in the cytosol into the endoplasmatic reticulum (ER) TAP: Transporter associated with Antigen Processing TAP1 and TAP2 form a membrane transporter in the endoplasmatic reticulum ATP-catalyzed transport of peptides form the cytosol into the ER Presentation by MHC class I 1. The generation of α:β T-cell receptor ligands MHC class I molecule do not leave the endoplasmatic reticulum unless they bind peptides What is presented on a cell’s MHC class I molecules in absence of infection? What changes in presence of a cytosolic (e.g. viral infection)? MHC class I a chain is only stable once it correctly folded and in complex with b2-microglobulin and a bound peptide several chaperons (e.g. calnexin, calreticulin) help in the folding and peptide loading of MHC class I Presentation by MHC class II Peptides that bind to MHC class II molecules are generated in acidified endocytic vesicles Peptides presented on MHC class II typically derive from proteins present in the extracellular space that have entered the cell through cellular uptake mechanisms (endocytosis, phagocytosis, macropinocytosis). This fits with the fact that MHC class II is mainly expressed on antigen-presenting cells (B cells, macrophages, dendritic cells) Proteins are degraded and MHC class II molecules loaded in acidified vesicles Presentation by MHC class II 1. The generation of α:β T-cell receptor ligands The invariant chain is cleaved to leave a peptide fragment, CLIP, bound to the MHC class II molecule Like any membrane protein, MHC class II molecules are first delivered into the endoplasmatic reticulum (ER) In the ER premature loading of endogenous peptides is prevented by the binding of the invariant chain (also called CD74), which is subsequently cleaved into a short peptide fragment termed CLIP CLIP serves as a “placeholder” until final peptide loading in the acidified vesicles.  Loading of antigenic peptides onto MHC class II molecules occurs in acidified vesicles In the acidified vesicles, HLA-DM (an-MHC-like molecule) associates with the MHC class II and facilitates the dissociation of CLIP and its exchange with other peptides  1. The generation of α:β T-cell receptor ligands “MHC class I typically presents peptides derived from proteins produced within the cell itself” …but there is an exception! => co-called cross-presentation by dendritic cells Scenario: Imagine an intracellular infection with Herpes virus which infects epithelial cells in the skin as well as trigeminal nerve endings. The virus is best fought by cytotoxic CD8+ T cells. But in case the virus does not infect professional antigen-presenting cells: How can virus- specific cytotoxic T cells become activated in first place? Revision from Chapter 1: Dendritic cells (DCs) are important for the induction of adaptive immunity in secondary lymphoid organs.  1. The generation of α:β T-cell receptor ligands “MHC class I typically presents peptides derived from proteins produced with the cell itself” …but there is an exception! => co-called cross-presentation by dendritic cells Scenario: Imagine an intracellular infection with Herpes virus which infects epithelial cells in the skin as well as trigeminal nerve endings. The virus is best fought by cytotoxic CD8+ T cells. But in case the virus does not infect professional antigen-presenting cells: How can virus- specific cytotoxic T cells become activated in first place? Cross-presentation: specialized types of DCs can capture extracellular antigen and load antigen-derived peptides onto MHC class I translocation of ingested proteins from the phagolysosome into the cytosol. There, proteins are degraded by the proteasome, peptides transported through TAP into the ER and loaded onto MHC-I transport of antigens from the phagolysosome into a vesicular loading compartment and loading onto mature MHC class I molecules (peptide exchange)  Summary: generation of α:β T-cell receptor ligands The ligand recognized by the TCR is a peptide bound to an MHC molecule MHC-I are synthesized in the ER and present peptides derived from proteins that are degraded in the cytosol by the proteasome. These proteins are imported into the ER by TAP. Only MHC-I molecules loaded with peptides travel to the cell surface. MHC-I present peptides to CD8+ T cells. MHC-II are synthesized in the ER, but peptide binding is inhibited by the invariant chain (IC). Peptide loading occurs in acidic endosomal compartments, where proteases cleave the IC, so MHC-II molecules can now bind peptides that derive from endocytosed proteins. MHC-II is mainly expressed by antigen-presenting cells (DCs, B cells, macrophages) and presents peptides to CD4+ T cells. Cross-presentation: Certain antigen-presenting dendritic cells are capable of loading peptides derived from exogenous (endocytosed) proteins onto MHC-I, to allow induction of CD8+ T cell responses. This process is known as cross- presentation. 2. The major histocompatibility complex (MHC) and its function Revision from Chapter 4: MHC class I MHC class II  2. The major histocompatibility complex (MHC) and its function HLA (human leukocyte antigen) nomenclature: Class I: HLA-A HLA-B HLA-C Class II: HLA-DR HLA-DP HLA-DQ Some further genes with relevance to antigen processing and are encoded the MHC locus (example: TAP proteins or LMPs (subunits of the immune proteasome)  2. MHC and its function Characteristics of MHC molecules: Polygenic 3 genes encoding MHC class I and 3 encoding MHC class II Polymorphic many different alleles co-dominantly expressed Remember: Allele = variant of a gene  2. MHC and its function Human MHC genes are highly polymorphic MHC class I MHC class II For many MHC class I and II genes there are more than 1000 alleles Most alleles are quite frequent, so chances are quite high that an individual has two different alleles on both homologous chromosomes. Since MHC molecules are co-dominantly expressed, this further increases the likelihood that two unrelated individuals differ in their MHC molecules The particular combination (“set”) or MHC alleles found on one chromosome is known as a haplotype Allele = variant of a gene  2. MHC and its function Exercise: MHC molecules 1) How many different types of MHC molecules do you expect on muscle cells or fibroblasts dendritic cells 2) What is the therapeutic relevance of MHC molecules? 3) MHC molecules are inherited from parents to children as haplotypes. Knowing this, what is the chance of two siblings having identical MHC molecules? HLA genetics MHC MHC haplotype haplotype of mother of father possible MHC haplotypes of children Þ 25% chance to share 2 HLA haplotypes with sibling Þ 50 % chance to share 1 HLA haplotype with sibling Þ 25% chance to share no HLA haplotype with sibling  2. MHC and its function Allelic variation in MHC molecules occurs predominately within the peptide-binding region Remember: Allele = variant of a gene  2) T-cell receptor gene rearrangement The most variable parts of the T-cell receptor (TCR) interact with the peptide of a peptide:MHC complex Remember: The TCR does not only bind the antigenic peptide but also the MHC molecule => The TCR binds the peptide: MHC complex The less variable CDR1 and CDR2 loops of a T-cell receptor mainly contact the relatively less variable MHC component of the ligand The highly variable CDR3 regions mainly contact the unique peptide component 22  2. MHC and its function T-cell recognition of antigens is MHC-restricted Antigen-specific T cell receptor recognizes a complex consisting of an antigenic peptide AND a self-MHC molecule The co-recognition of a (foreign) peptide and an MHC molecule is known as MHC-restriction The phenomenon of MHC-restriction was discovered by Peter Doherty and Rolf Zinkernagel, who received the Nobel Prize for this discovery in 1996.  The polymorphism of MHC molecules particularly affects amino acid residues in the peptide binding cleft and TCR-contact region Remember (Chapter 4): The TCR gene is rearranged from V, (D) and J segments. The hypervariable regions of the CDR1 and CDR2 (red) are encoded in the V- segment, whereas the CDR3 (red) is generated at the junctions of the gene segments. => T cell receptors (TCRs) frequently make contact with MHC molecules via the CDR1 and CDR2 of V region genes => MHC and TCRs need to complement (“match”) each other for binding. This is taken care of during T cell development “positive selection” in the thymus (see Chapter 8) Summary: The Major Histocompatibility Complex and its function MHC complex of genes consists of a linked set of genetic loci encoding many of the proteins involved in antigen presentation to T cells (most notably MHC class I and class II proteins) MHC class I/II molecules are highly polymorphic. A T cell only recognizes peptide antigen bound to one particular allelic variant of an MHC molecule. => “T cells are MHC-restricted” The amino acid sequence differences between different alleles are concentrated in the peptide-binding region (and region making contact with the T cell receptor) In addition, MHC molecules are also polygenic (3 genes encoding MHC-I and 3 versions of MCH-II molecules) and expressed co-dominantly: => a cell can express up to 12 different MHC molecules!