Antigen Presentation to T cells PDF 2024

Antigen Presentation to T cells Dr Allison Imrie Routes of antigen entry Microbial antigens commonly enter through the skin and gastrointestinal and respiratory tracts Antigens are captured by dendritic cells and transported to regional lymph nodes Antigens that enter the bloodstream are captured by...

Antigen Presentation to T cells Dr Allison Imrie Routes of antigen entry Microbial antigens commonly enter through the skin and gastrointestinal and respiratory tracts Antigens are captured by dendritic cells and transported to regional lymph nodes Antigens that enter the bloodstream are captured by antigen-presenting cells in the spleen Processed peptide is shown (presented) to T cells by antigen-presenting cells The three major types of antigen-presenting cells for CD4 + T cells function to display antigens at different stages and in different types of immune responses T cells recognize peptide antigen in the context of MHC molecules Pathways of antigen processing and presentation In the class I MHC pathway (top panel), protein antigens in the cytosol are processed by proteasomes, and peptides are transported into the ER, where they bind to class I MHC molecules. In the class II MHC pathway (bottom panel), protein antigens that are degraded in lysosomes bind to class II MHC molecules CTL, Cytotoxic T lymphocytes; ER, endoplasmic reticulum; TAP, transporter associated with antigen processing Role of dendritic cells in antigen capture and presentation A, Immature dendritic cells (DCs) in the skin (Langerhans cells) or dermis (dDCs) capture antigens that enter through the epidermis and transport the antigens to regional lymph nodes. During this migration, the dendritic cells mature and become efficient APCs B, The table summarizes some of the changes during DC maturation that are important in the functions of these cells. Half-life is an estimate of how long the molecules are expressed on cells [The number of surface molecules is per class II--expressing cell] ICAM-1, Intercellular adhesion molecule 1; IL-12, interleukin-12; MHC, major histocompatibility complex. DCs are divided into several subsets based on phenotypes and functions Conventional (or classical) DCs (cDCs) are present in most epithelia that interface with the external environment, such as the skin and the intestinal and respiratory tracts, and in tissues, and are enriched in lymphoid organs. cDCs capture antigens and transports them to secondary lymphoid organs and present antigen to naive CD4 + and CD8 + T cells. cDCs are divided into two groups: Type 1 cDCs (cDC1) are especially efficient at transferring ingested antigens from vesicles into the cytosol. This is an essential step in the process of cross-presentation Type 2 cDCs (cDC2) are the major DC subset that presents captured antigens to CD4 + T cells: the subset that is most important for initiating responses Plasmacytoid DCs (pDC) are the major source of type I IFN and are essential for innate immune responses to viruses. pDCs also may capture antigens in the blood and transport them to the spleen. Monocyte-derived DCs (moDC) can be induced to develop from monocytes under inflammatory conditions. Their roles in immune responses are not clear. Langerhans cells of the epidermis were one of the earliest DCs identified. These cells are related to tissue-resident macrophages and develop early in life from progenitors in the yolk sac or fetal liver and seed the skin. Their function is similar to that of cDC2 Peptides that may bind to MHC Class I are actively transported from the cytosol to the endoplasmic reticulum MHC Class I molecules associate with endogenous peptide antigens synthesized within the cell These antigens may be derived from cytoplasmic cellular proteins, from intracellular pathogens, or from tumour proteins The proteosome digests proteins to produce peptides which then enter the ER to associate with MHC-I molecules TAP1 (transporter associated with antigen processing) and TAP2 proteins translocate peptides 8-16 aa long into ER lumen Some additional enzyme-mediated trimming occurs in ER Peptides too long to bind to MHC-I molecules can be trimmed with an aminopeptidase, endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP) MHC-I Newly syntheised MHC-I ⍺ chains assemble in the ER with membrane-bound calnexin Binding of β2m dissociates calnexin; the partly folded MHC molecule then binds to TAP by interacting with tapasin Chaperone molecules bind and stabilize the complex Even in the absence of infection there is a continuous flow of peptides from the cytosol into the ER Defective ribosomal proteins 9DRiPs) and proteins marked (ubiquinated) for destruction are transported into the ER by TAP MHC-I MHC-I molecule is retained within ER until it is released by binding with a peptide – this completes the folding of the MHC molecule Once a peptide has bound to the MHC, the peptide/MHC complex leaves the ER and is transported through the Golgi apparatus to the cell surface The class I major histocompatibility complex pathway of antigen presentation β2m, β2-Microglobulin; ERAP, endoplasmic reticulum–associated peptidase; ER, endoplasmic reticulum; TAP, transporter associated with antigen processing; Ub, ubiquitin Peptides that bind to MHC Class II molecules are generated in acidified endocytic vesicles Extracellular foreign antigens – such as bacteria – are taken up by APC pH of endosome decreases, activating proteases which degrade engulfed material into peptide fragments MHC-II molecules leave ER bound for cell surface via the endosomal pathway Interact with vesicles containing peptides MHC molecules which do not bind peptide are degraded in low pH of vesicle MHC-II MHC-II ⍺ and β chains (yellow) are found in ER complexed to the invariant chain Ii polypeptide (green) The Ii is cleaved to small fragments one of which – the Class II-associated invariant peptide, CLIP (red) is located in the groove of the MHC-II molecule until replaced by peptide destined for presentation The MHC ⍺β/Ii complex is transported through the Golgi to an endosomal compartment, MHC Class II compartment MIIC The Invariant Chain Ii directs newly synthesized MHC-II molecules to acidified intracellular vesicles ER contains many unfolded or partly folded polypeptide chains, so a mechanism is needed to prevent their binding to the open-ended MHC-II molecule peptide-binding groove Newly synthesized MHC-II molecules are assembled with Ii in the ER, and a subunit lies within the groove and prevents binding of other peptides Ii targets delivery of MHC-II to a low pH endosomal compartment where peptide loading can occur The MHC Class II-like molecule HLA-DM facilitates the loading of antigenic peptides onto MHC Class II Ii binds to newly synthesised MHC-II and blocks binding of peptides and misfolded proteins found in ER and during transport of MHC-II Ii is cleaved in the vesicles to leave the CLIP fragment still bound to MHC-II CLIP is released from MHC-II/CLIP complex by binding of HLA-DM Pathogen peptides derived from endocytosed antigens can now bind to MHC-II The MHC-II/peptide complex travels to cell surface where it is expressed The class II major histocompatibility complex pathway of antigen presentation CLIP , Class II–associated invariant chain peptide; ER, endoplasmic reticulum; HLA, human leukocyte antigen; I i , invariant chain The functions of class II major histocompatibility complex–associated invariant chain and human leukocyte antigen DM MHC-II with bound invariant chain, or CLIP, are transported into late endosomes and lysosomes, where the Ii is degraded and the remaining CLIP is removed by the action of DM Antigenic peptides generated in the vesicles are then able to bind to the MHC-II molecules CIIV, Class II vesicle; ER, endoplasmic reticulum; I i , invariant chain Presentation of extracellular and cytosolic antigens to different subsets of effector T cells A, Cytosolic antigens are presented by nucleated cells to CD8 + cytotoxic T lymphocytes (CTLs) , which kill (lyse) the antigen-expressing cells B, Extracellular antigens are presented by macrophages or B lymphocytes to CD4 + helper T lymphocytes, which activate the macrophages or B cells and eliminate the extracellular antigens Cross-presentation: presentation of exogenous antigens on MHC Class I molecules to initiate CD8+ T cell responses Antigen processing and presentation via MHC-I and MHC-II pathways Dendritic cells cross-present exogenous antigen for presentation by MHC-I molecules to activate CD8+ T cells The epitopes of complex proteins that elicit the strongest T cell responses are the peptides that are generated by proteolysis in APCs and bind most avidly to MHC molecules If an individual is immunized with a protein antigen, in many instances the majority of the responding T cells are specific for only one or a few linear amino acid sequences of the antigen. These peptides are immunodominant epitopes or determinants. The proteases involved in antigen processing produce a variety of peptides from natural proteins, and only some of these peptides possess the characteristics that enable them to bind to the MHC molecules present in each individual. Similarly, peptides produced by mutated genes in cancers are analysed for their ability to bind to the MHC-I molecules in each patient with cancer. The ones that bind are most likely to stimulate antitumor immunity in that patient. Protein antigens are processed to generate multiple peptides; immunodominant peptides are the ones that bind best to the available class I and class II MHC molecules APC, Antigen-presenting cell; MHC, major histocompatibility complex Summary: Features of the antigen processing and presentation pathways ‘endogenous’ and ’exogenous’ are terms also used for ‘cytosolic’ and ‘endosomal’ antigens Summary: Features of the antigen processing and presentation pathways