Antigen Processing and Presentation - MHC Canvas 2024 PDF

Antigen Processing & Presentation aka MHC Dr. Sreepoorna Pramodh [email protected] c.uk wledgements: Dr Alba Llibre and Dr Jenny Marshal Innate vs Innate immunity The immune system you Adaptive imm...

Antigen Processing & Presentation aka MHC Dr. Sreepoorna Pramodh [email protected] c.uk wledgements: Dr Alba Llibre and Dr Jenny Marshal Innate vs Innate immunity The immune system you Adaptive immunity Extremely variable Adaptive are born with Does not change during receptor set Extreme ability for clonal immunity life Fixed number of expansion B cells adapt to preformed pathogen completely new recognition receptors structures Advantages: Advantage: – Fast – Can react to anything – Many cells – Immunological memory Disadvantage: Disadvantage: – may not be able to react – Slow to something new The innate and adaptive immune interact Two types of adaptive immune cells: B lymphocytes produce antibody T lymphocytes – of which, two subsets B Cytotoxic T cells: Kill infected cells (CD8+) Cytotoxic Helper T cells: Co-ordinate the immune response T cell and help other immune cells (CD4+) T Helper T cells are very powerful cells and so areT cell T highly regulated In this lecture we’ll learn how the innate immune system talks to T NK cells: MHC (major histocompatibility  MHC What is MHC? Class I (Major Histocompatibility Complex) Complex of proteins Presents linearised peptides from chopped up pathogens to T cells This is a key way T cells are regulated – they can not respond to anything otherwise Comes in two types – I and II (one and two) The human version of MHC is called HLA (human leukocyte antigen) There are three types of each human HLA HLA Class 1- HLA A, HLA B, HLA C HLA Class 2- HLA DP, HLA DQ, HLA DR  MHC-Types MHC Class II MHC Class I Present on antigen presenting Present on all nucleated cells cells- dendritic cells, Structure- α1, α2, α3 and β2 macrophages, B cells macroglobulin chain Structure- α1, α2 chains and β1 Has 1 transmembrane and β2 chains domain Displays endogenous Has 2 transmembrane domains (intracellular antigens/viral Displays exogenous peptides peptides) Recognized by CD4 Helper T Recognized by CD8 cytotoxic T cells cells TCR TCR CD4 CD8 α βMHC II α MHC I Dendritic cell Different pathogens live in different places… need different responses Stimulating the correct T cell, in the right way, helps do this. (Different types of T cells will be covered in a MHC Class following lecture!). II MHC Class CD4 I Helper T CD8 T Cells Cells All responses need T cell help So, different T cells = different MHC type? YES! We have two types of T cells and two paths of antigen processing CD4+ T cells help the CD8+ T cells protect adaptive and innate against intracellular response infections and cancer Class II MHC molecules The class I MHC pathway present antigen to CD4+ T handles intra-cytoplasmic cells and generally handle antigens exogenous antigens Reading: Janeway’s Immunobiology 9th Edition,  A term most commonly used when referring to cells that present processed antigenic peptide and MHC class II molecules to the T‐ Antigen cell receptor on CD4+ T‐cells (Examples- dendritic cells, macrophages, B‐ cells) Presenting Cells Dendritic cells form a crucial link between the innate immune response and the (APCs) adaptive immune response In certain situations, macrophages and B cells can also act as antigen-presenting cells, but dendritic cells are the cells that are specialized in initiating the adaptive immune response. How do we join up the innate and the adaptive response? Skin Trachea Cervix Courtesy of Dr. Leopoldo Flores-Romo Dendritic cells! Laboratory of Cellular Biology CINVESTAV. Mexico. Constantly sample the environment In infection - activated by PAMPs Antigen exposure Change the receptors that anchor Immature DCs them in the tissue and migrate to the nearest lymph node Migrating DCs in afferent lymphatic vessels Activated Mature DCs T cells Steinman, R http:/lab.rochefeller.edu/steinman/ imagegallery  antigen presentation; activation of adaptive immunity Oxidative killing pathogen killing chemokines dendritic cells NETosis phagocytosis Innate recognition (PRRs), Tissue-resident phagocytosis macrophage inflammatory macrophage Histamine; vasodilation chemotaxis Monocytes and Yeast or bacteria neutrophils PRR Signalling Triggers Dendritic Cell Activation and Promotes An Adaptive Immune Response Tissue Pathogen Dendritic cell Lymph node Proliferation Adaptive immunity  Why do dendritic cells go to the LN? A quick anatomy re-cap Each B and T cell in your body can only respond to one antigen The antigen each one can respond to is unique If they stayed in one place they’d always be in the wrong place. If they were in your blood they’d also be impossible to find. SO! They circulate between the lymph nodes and spleen of your body As the dendritic cells stay in one place, the T cells will always find them! Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". Circulation of T and B cells ensures that you have an adaptive immune response The circulation of T and B cells from LN to LN means that they will pass through the lymph node where the DC is And if they match you will get an immune response   Where do DCs meet T cells in the LN? The lymph node has different areas to allow B and T cells to find antigen Blood vessel Antigen presentation by DCs to naïve T cells takes place in T cell zone the lymph node. DCs / B cells Steinman, et al. Immunol Reviews. 1997, 156: 25- 37. You need MHC at all parts of the T cell “journey” To make T cells in the first place The start (lymph node) To activate T cells To help B cells produce antibody In the periphery (where your infection is) To help cells fight the infection Quick reminder! To get to the LN dendritic cells must be activated by PAMPs/DAMPs - Stops random T cell responses TCR TCR T cells can only be activated CD4 CD8 by MHC with a peptide from a pathogen attached - Makes the response MHC II MHC I α β α specific Activated Dendritic cells in the LN express both MHC types Dendritic cell and will be able to activate (or an antigen presenting cell – APC) both types of T cell Majumdar et al. (Resonance The physical differences between MHC – I & II MHC MHC Class Class I II The Spruce / Laura Donovan β α1 α3 α1 1 β α2 β 2m α2 2 MHC Class I: MHC Class Alpha chain II: usually 8–10 13–25 residues + beta2 Alpha residues microglobulin chain  Peptides are held in place by anchor residues ch MHC uses hydrogen bonds to the amino acids in the peptide to hold it in place erent MHC will preferentially bind to different peptides MHC I MHC II Hydrophob’ Hydrophob’ Basic/polar ydrophobic e charge Negativ aromatic  MHC Class I MHC Class II MHC polymorphism Individual MHC alleles can differ by up to 20 amino acids - each variant protein is quite distinct Differences are localized to exposed surfaces of the outer domain of the molecule and to the peptide-binding groove in particular The polymorphic residues that line the peptide-binding groove determine the peptide-binding properties of different MHC molecules And you have more than one MHC on your cells Human MHC II Human MHC I Three alleles of MHC I and MHC II available on the α and β chains chromosome Co-dominantly expressed You can personally present a wide range of peptides to your T cells Human Human MHC I MHC II HLA-A HLA-DP HLA-B HLA-DQ HLA-C HLA-DR This is important at an individual & population level! During an infection pathogens may mutate or phase shift e.g. RNA viruses This means your immune system now has new antigens to present Variety is better! Highly polymorphic HLA class I and class II loci (red) compared to those who are homozygous for one locus (yellow) or for two or three loci (blue). Global distribution of specific HLA alleles Zhou et al. Hum Genet 2022  Human MHC genes are clustered… They are all expressed when the cell is activated LMP – alternative subunits of the proteosome TAP – needed to let peptides into the golgi  How do we get this antigen on our MHCs? nly want peptides from pathogens. ut your golgi apparatus is full of tempting proteins… MHC Any old peptide Chaperone proteins trying to stop autoimmunity And how do you get onto the correct MHC? Two primary antigen processing pathways, overview  The MHC class II antigen processing pathway How do we take proteins from outside the cell and put them on MHCII? 1. Activate the cell and get the antigen in (lecture 1) 2. Digest the antigen (see lecture 2) 3. Fuse the endosome with a vesicle containing MHCII 4. Get those peptides onto the MHC II OBVIOUSLY, more complicated than that! Need to prevent your MHCII picking up any spare peptides on the way… Invariant chain https://www.nature.com/articles/nri3339 Class II MHC Binds Invariant Chain Invariant chain is a molecule that interacts with MHC II as they are being made It protects peptide binding cleft of MHC II and prevents binding of nonspecific peptides It traffics MHC II out of endosome α, β, and invariant chain interact with chaperone and only when MHC and invariant chain fold properly, can they The role of the Invariant Chain (and CLIP) MHC Class MHCs II Transport and Invariant chains Peptide Loading MHC Class II Antigen Processing & Presentation n.b! MHC II expression only happens in immune cells that are can phagocytose/endocytose They are the ones that have PRRs need to respond to infection And will need help doing so Things going wrong inside a cell? MHC I e.g. infections (viruses, bacteria) but also oncogenesis can happen to any cell so Nearly all cells express MHC I to : Tell cytotoxic (CD8) T cells that they need to be killed AND (importantly) DCs will express both MHC I and MHC II to Get T cell help and antibody to help fight infection Difficult! Pathogens don’t want this to happen Activating Cytotoxic T Cells (CD8s) Most nucleated cells express class I MHC and can present antigen by the endogenous route This is the MHC recognised by cytotoxic CD8+ T cells Cytotoxic T cells kill infected cells  The MHC class I antigen processing pathway How do we get antigens onto MHC I? Aka, how do we get already made proteins from the cytoplasm into our protein What about proteins from inside production pathway? our cell? Conventional protein 1. Break down the protein with a processing takes place in proteasome (CBB year 1) vesicles 2. Get that into your ER - that’s where your MHC I will 3. Somehow, put only those be peptides onto MHCI 4. Transport that MHC I out to But we are taking proteins the surface from the cytoplasm… so we need OBVIOUSLY, more complicated than that! 1. A way into a vesicle 2. A way to chop up that protein The proteasome - how we chop up proteins Your cells need to be able to get rid of unneeded or faulty proteins. To do this they use the proteasome - Highly conserved structure! Found in archaebacteria! All the proteins in your cell go through this pathway… including any from infections! Your MHC I pathway uses this default pathway Schild & Ramensee: Nature (2000) 404:709-710 Class I MHC Assembly Involves a Network of ER- resident Chaperones MHC I is constructed in the ER It’s unstable until β2m is bound so calnexin stabilises the molecule Class I MHC Assembly Involves a Network of ER- resident Chaperones How do you stop the new MHC I binding to any old thing? Hide it! And then bind it to the TAP proteins Class I MHC Assembly Involves a Network of ER- resident Chaperones Your peptide needs to bind with a high enough affinity in order for the MHC I to be released Class I MHC Assembly Involves a Network of ER- resident Chaperones MHC Class I Antigen Processing & Presentation But… Not every virus infects DCs (Tropism) If we need MHC I to present viral antigens how are CD8 cells primed against viruses that do not infect dendritic cells? And how do we help B cells produce antibody to intracellular infections? Dendritic cells can undergo Cross- presentation This is controlled by TLR signals that optimise presentation of antigens from infectious agents Cross presentatio n in brief: Who gets to talk to T cells? - Key antigen presenting cell (APC) is the dendritic cell Starts the adaptive immune response But other cells need to do so! To show they are infected (MHCI) To be activated during the innate response by a T cell † = only mircroglia – a type of brain-based macropha Key concepts you should be happy with: Dendritic cells are essential to start the T cell response (control!) A diversity of MHC is important for individuals and populations! MHC I and II processing pathways, and what they are for What MHC is on what cell And, to be built on over the next few lectures: MHC is the way that T cells are activated Each T cell has a unique TCR that can only recognise one peptide So they will only respond to the right antigen – specific response= Reading: Janeway’s Immunobiology 9th Edition, Chapter 6 T cell subsets - summary CD4 T cells are the helper T CD8+ T cells are the cytotoxic cells, which assist other blood T cells, which kill viral-infected cells to produce an immune and tumour cells. response. Express CD8 glycoprotein on the Express CD4 glycoprotein on cell membrane. the cell membrane. Recognise antigen on the Recognise antigen on the surface of all nucleated cells surface of professional through MHC-I. antigen-presenting cells (APCs) through MHC-II. What happens next? Activated T cells, antibody, recovery Any questions?