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Antigen processing and presentation • • • • • • Endogenous antigen presentation pathway Exogenous antigen presentation pathway Microbial evasion strategies Cross-presentation Lipid presentation Transcriptional regulation of MHC (review) peptide size: 8-10aa 10-20aa any nucleated cell * professional APC * Janeway’s Imunolobiology 8th ed (© 2012 by Garland Science, Taylor & Francis Group, LLC) (* Naive T cell activation is a topic of another lecture) Some questions can emerge: • How could the peptide choose the appropriate MHC molecule? (MHC I MHC II) • Where the peptides are generated? • Where and how can bind the peptides to the MHC molecules? • Is there a possibility that a more fit peptide could replace the MHC bound peptide on the cell surface? General properties of the MHC-peptide interaction: • MHC molecules can be in a receptive, ”open” conformation until the appropriate peptides bind to them. • The receptive conformation is maintained by the chaperones and the biochemical properties (e.g. pH) of the peptide loading compartment. • Appropriate peptide can induce the conformational change of the MHC molecules. (Appropriate peptide has appropriate binding motif, which allow effective binding to the MHC molecule see the previous lecture) • The bound peptide stabilizes the ”closed” conformation • ”Closed” MHC molecules can detach from the chaperones and reach the cell surface The role of the MHCs’ chaperones • Stabilizing “empty” MHC molecules Empty MHC molecules could become denatured, aggregated and rapidly degraded without chaperones • Retaining or transporting the MHC molecules in the appropriate peptide loading compartment e.g. ER chaperones contain ER retention/targeting signals • Stabilized empty MHC molecules will bind the best fit peptide A better fit peptide can displace the weakly bound peptide (competition) PEPTID EDITING Endogenous antigen presentation pathway antigen processing for MHC class I molecules ENDOGENOUS Ag PRESENTING PATHWAY CELLULAR AND MOLECULAR IMMUNOLOGY 8th ed. (Abbas, AK – Lichtman, AH – Pillai, S) (Elsevier, Saunders 2015) Synthesis and peptide binding of MHC I molecules Freshly translated ERAAP can trim the peptides to fit Janeway’s Imunolobiology 8th ed © 2012 by Garland Science, Taylor & Francis Group The chaperon complexbound MHC molecule is ready for peptide binding Through the Golgi-network The best fit peptide wins the MHC: PEPTIDE EDITING The function of the proteasome • A cell can contain ~30000 proteasomes (1% of the overall protein mass) • Proteasomes can be found in the cytosol and the nucleus unfolding peptides (Molecular Biology of the Cell 5th ed@ 2008, 2002 by Bruce Alberts, Garland Science) Proteasomes degrade proteins to peptides Proteasomal peptide products could be tailored for MHC I binding 20S subunit of the constitutive proteasome protease subunits The Immune System 4th ed Parham,P (© 2015 by Garland Science, Taylor & Francis Group, LLC) http://www.rcsb.org/pdb/explore.do?structureId=4R3O The ”Immune proteasome” IFN- • new protease subunits replace the others (LMP2, LMP7, MECL-1) • produced peptides are more optimized for MHC I binding protein cleavage preference is changed: hydrophobic or basic amino acid on the C-terminal of the peptide TAP complex transports the peptides into the ER Prefered peptides (for transport): • 8-16 aa length • hydrophobic or basic amino acids at the C-terminal • top view side view Janeway’s Imunolobiology 8th ed (© 2012 by Garland Science, Taylor & Francis Group, LLC) no proline in the first 3 positions (from the Nterminal) The preferences of the TAP correspond to the cleavage specificity of the immune proteasome and the general binding preferences of MHC class I molecules Exogenous antigen presentation pathway antigen processing for MHC class II molecules EXOGENOUS Ag PRESENTING PATHWAY CELLULAR AND MOLECULAR IMMUNOLOGY 8th ed. (Abbas, AK – Lichtman, AH – Pillai, S) (Elsevier, Saunders 2015) Newly translated MHC II αβ dimers bind to Ii (invariant chain, CD74) chaperon nonameric complex Multimerisation generally turns the low affinity interactions to higher avidity interaction between the complexes α-β-Ii triplex • A part of the Ii chain can fit into the peptide binding site of various MHC II molecules • The bound Ii is blocking the binding site and prevents the binding of ER resident peptides • Ii have endosomal localisation signal sequence Janeway’s Imunolobiology 8th ed © 2012 by Garland Science, Taylor & Francis Group MHC II – Ii complexes travel through the Golgi-apparatus into the endosome The assembly of the [MHC class II molecule – exogenous peptide] complex CLIP peptide peptide editing Janeway’s Imunolobiology 8th ed © 2012 by Garland Science, Taylor & Francis Group CLIP - Class II-associated invariant chain peptide proteases: e.g. cathepsins HLA-DM is a monomorphic MHC class II-like chaperon, which helps in the peptide editing The peptid editing of HLA-DR by the help of HLA-DM in the endo-lysosomal compartment cell surface (6) HLA-DRα DM detachment CLIP best fit antigenic peptide HLA-DRβ CLIP detachment starts in the acidic endolysosomal compartment antigen derived peptide DM stabilise the ”empty” DR Wouter Pos et al.: Cell 2012, 151, 1557–1568 The peptide binding (editing) of the MHC II molecules could take place in a multivesicular/multilamellar endo-lysosomal vesicle: named MIIC or CIIV compartment CIIV – Class II Vesicle or MIIC – MHC class II Compartment Immunity, Vol. 22, 221–233, February, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.immuni.2005.01.006 Immuno-electron-microscopy, double immunogold labeling small dots: HLA-DM (10nm nanogold) larger dots: HLA-DR (15nm nanogold) The compartment of the MHC II peptide loading is defined by the presence of HLA-DM Defficiencies of the antigen processing pathways • TAP deficiency: few intra ER peptides low cell surface MHC I expression • tapasin deficiency: altered peptide editing alteration in the MHC I presented peptide repertoire (altered peptide set). More ER derived, fewer cytoplasm (protesome) derived peptides. • B2M (β2 microglobulin) deficiency: impaired MHC class Ia and class Ib expression (e.g. FcRn, CD1, MR1 !) • Ii (invariant chain, CD74) deficiency: alteration in the MHC II presented peptide set (predominant presentation of endogenous peptides) - Altered MHC expression or peptide presentation directly influence the development or the function of the T lymphocytes and NK cells. - This indirectly influences almost all cells of the immune system and the immune response. Pathogens try to interfere with the antigen presentation! An immune evasion strategy of the Epstein-Barr virus (EBV) The schematic gene map of the EBV and the targets of the EBV specific CTL response + LMP2 ± (?) EBNA-LP ± ++ ++ ++ EBNA2 EBNA3A EBNA3B EBNA3C EBNA1 Jhet C W W W W W W H F Q U P O MS L E Z R K B G D W WW W W Y BHRF1 ++ BMLF1 BMRF1 ++ BZLF1 ++ + LMP1 TXV I A Nhet BARF0 ++ • “Lytic antigens” and EBNA3 nuclear proteins are the main targets of the polyclonal CTL response • The processing of endogenous EBNA1 is ineffective EBNA1 contains repeated Glycine-Alanine sequences which inhibits the proteasomal degradation ineffective antigen presentation × EBNA1 expression is enough to maintaining the latent viral phase the virus is invisible for the CTL immune response in the viral latent phase Microbes can use different immune evasion strategies Janeway’s Imunolobiology 8th ed © 2012 by Garland Science, Taylor & Francis Group MHC ubiquitination inhibition of the chaperones inhibition of the TAP function × Viral strategies against antigen presentation Immunoevasins Janeway’s Imunolobiology 8th ed © 2012 by Garland Science, Taylor & Francis Group Pathogens try to use various mechanisms to evade the presentation of their antigens Pathogens try to evade the immune response by disabling the MHC I expression of the host cells NK cells possess various inhibitory NK cell receptors which recognise different MHC class I molecules. Decreased or missing MHC I molecule expression on the target cells results NK cell activation. • Absence of polymorphic MHC class I molecules: - HLA-C alleles are potent NK inhibitors (in most of cases) - Lots of HLA-A and HLA-B alleles could also inhibit the NK cell activation with different efficiency • Absence of HLA-E is an indirect indicator of the missing HLA class I translation: HLA-E is a potent NK inhibitor (by NKG2A:CD94). HLA-E cannot leave the ER without binding signal peptides from the classical polymorphic MHC I. Weak HLA-A, -B, -C translation weak HLA-E expression. • activatory signals override the inhibitory signals • NK cell activation killing the cells with ”missing self” (see in the previous lectures also) MHC class II molecules present both exogenous and endogenous peptides • If a peptide in the ER is able to bind to an MHC II molecule with high enough affinity, it will compete the invariant chain. The Ii-MHC II complex is not formed: - MHC II molecules can’t reach the endolysosomal compartment without the Ii - MHC II travels to the cell surface with the bound peptide, similarly to the MHC I-peptide complex • Self proteins and peptides can reach the endolysosomal system (ERGolgiMIIC). Their processed peptides can be bound by the MHC II molecules as in the case of the engulfed antigens. • Dead self-cells can be engulfed by phagocyte APC-s. Any protein derived peptide in the endosome can have the opportunity to be presented by the MHC II molecules. Even cytoplasm derived peptides (from the dead cells) can be presented exogenously by MHC II molecules this way. • MHC II molecules can bind (exchange) extracellular peptides on the surface of the APC, and they can travel back into the endolysosomal system (cell surface CD74 helps) Is special circumstances the MHC I molecules must present exogenous protein derived peptides: Cross-presentation: Cross-presentation: exogenous antigen(!) MHC I molecule(!) • Naive, antigen specific CD8+ T cells need activation by dendritic cells to mature CTL. • Lots of viruses are not able to infect DC, so direct MHC I presentation cannot be achieved • Specialised DC are able to present exogenous antigens by MHC I molecules Effector CTL CELLULAR AND MOLECULAR IMMUNOLOGY 8th ed. (Abbas, AK – Lichtman, AH – Pillai, S) (Elsevier, Saunders 2015) • Endocytosed viral antigens should reach the cytosol to enter the conventional endogenous antigen presentation pathway Lipid presentation by CD1 molecules (MHC-like class Ib) • CD1 synthesis and folding is similar to the conventional MHC I molecules • Lipid transfer proteins (LTP) in the ER or the endosomal system helps to bind or exchange the lipids in the binding site of the CD1 molecules: “LIPID EDITING”) • They can recycle from the cell surface and bind new lipids in the endosomal system NATURE REVIEWS IMMUNOLOGY VOLUME 5 | JUNE 2005 | 485- CD1 molecules can present both endogenous and engulfed exogenous lipids The IFN-γ mediated transcriptional regulation of MHC class I and class II molecule expression and its receptor chains and its receptor chains BioFactors, 42(4):349–357, 2016 • • IFN-γ induced MHC trans activator molecules mediate effective activation of the MHC genes Pro-inflammatory cytokines, or PRR-s can directly or indirectly increase the MHC expression (NF-kB pathway or IFN pathway through the trans activators) The NOD-like trans activators of the MHC genes mediate the formation of large enhanceosome complexes (NLRA) BioFactors, 42(4):349–357, 2016 • The large enhanceosomes can integrate different transcription factors and chromatin remodelling proteins for effective gene activation • CITA enhanceosomes increase the expression of the MHC I presentation pathway’s genes: HLA-A, -B, -C, HLA-E, TAPs, B2M, proteasome subunits, … • CIITA enhanceosomes bind to the promoter regions of the MHC II presentation pathway’s genes: HLA-DR, -DP, -DQ, -DM, -DO, Invariant chain (Ii) and could influence the MHC I genes also in some professional APC-s. MHC II expression of human monocyte derived dendritic cells - before the activation/maturation - after the activation/maturation (by TLR7/8 ligands) The histograms below show the results of a flow cytometric measurements ~10 fold difference Inflammatory mediators can increase the MHC molecule expression of the cells • Strong inflammatory environment results the expression of MHC II molecules by non-professional antigen presenting cells also (e.g. endothelia) • IFN-γ induces MHC II expression of the IFN-γ receptor expressing cells (e.g. helper T cells after their activation) Ectopic expression of MHC II molecules exacerbate (increase the severity) of the transplant rejections. non-activated activated ANTIGEN PROCESSING AND PRESENTATION short incomplet summary (exogenous Ag.) (endogenous Ag.) 8-10aa 10-20aa (CTL) (helper) (CIIV/MIIC) CELLULAR AND MOLECULAR IMMUNOLOGY 8th ed. (Abbas, AK – Lichtman, AH – Pillai, S) (Elsevier, Saunders 2015) Themes and topics (you should know): • Endogenous antigen presentation pathway • Exogenous antigen presentation pathway • Cross-presentation • Main viral evasion strategies • Lipid presentation • Transcriptional regulation of MHC various terms (you should know): • • • • • • • • • • • • • • • • • • • protein, peptide cellular compartments MHC I, MHC II molecules proteasome, immunoproteasome TAP (1, 2) chaperon tapasin signal sequence/peptide protein targeting/sorting Ii (invariant chain), CLIP HLA-DM endosome, MIIC/CIIV peptide editing cross-presentation ”missing-self” theory lipid transport proteins (LTP) “lipid editing” term NLRC5, CIITA trans activators CITA, CIITA enhanceosomes as terms The Immune System (P. Parham, 4th ed): chapter 5-10 – 5-17 (p126-134), 12-14 – 12-17 (p352360), 5-20 (p138)