Antigen processing and presentation...Yoshinori Ohsumi "for his discovery of mechanisms for...
Transcript of Antigen processing and presentation...Yoshinori Ohsumi "for his discovery of mechanisms for...
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Università degli Studi di Messina
Antigen processing and presentation
Guido Ferlazzo
SIICA
School of
Immunology
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PAMP: Pathogen Associated Molecular Pattern
PRR: Pattern Recognition Receptors
PRR-PAMP interactions
Activation of Innate Immunity
Cosa induce l’attivazione dell’immunità acquisita
(cellule T e cellule B)?
Gli antigeni
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Un antigene e’ una sostanza che, introdotta in un
organismo, e’ capace di reagire specificamente con
anticorpi e/o recettori di membrana dei linfociti T o B
Un antigene e’ immunogenico se induce una
reazione immunologica.
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Un antigene e’ una sostanza che, introdotta in un organismo, e’ capace
di reagire specificamente con anticorpi e/o recettori di membrana linfocitari
Un antigene e’ immunogenico se induce una reazione immunologica
Peso molecolare, solubilita’, capacita’ di essere fagocitato
Dose e via di ingresso/somministrazione
Estraneita’ (non-self)
Proteine
Polisaccaridi
Lipidi
Acidi nucleici
Natura chimica
degli antigeni
I linfociti non riconoscono ne’ interagiscono con l’intera molecola immunogenica, ma
riconoscono dei siti limitati chiamati epitopi o determinanti antigenici, che si legano
a recettori linfocitari di membrana oppure ad anticorpi secreti.
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B cell receptor T cell receptor
Recettori linfocitari per l’antigene
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Confronto fra il riconoscimento dell’antigene effettuato
dal linfocita B e dal linfocita T
Caratteristiche Linfocita B Linfocita T
Interazione con Processo binario Processo ternario
l’antigene tra Ig ed Ag tra TCR, Ag, MHC
Legame di antigeni Si No
solubili
Coinvolgimento di Non necessario Necessita presentazione
molecole MHC dell’antigene
Natura chimica Proteine, lipidi, Principalmente proteine,
degli antigeni polisaccaridi a volte lipidi presentati da
molecole MHC-simili
Proprieta’ Accessibile Peptidi interni lineari
dell’ epitopo aa sequenziali e prodotti dalla processazione
non sequenziali dell’antigene
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I linfociti B riconoscono determinanti conformazionali ed esterni dell’antigene
Epitopi B: formati da aa localizzati
in punti diversi della catena amino
acidica ed avvicinati dal ripiegamento
della molecola
Epitopi T: aa in seguenza
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Confronto fra il riconoscimento dell’antigene effettuato
dal linfocita B e dal linfocita T
Caratteristiche Linfocita B Linfocita T
Interazione con Processo binario Processo ternario
l’antigene tra Ig ed Ag tra TCR, Ag, MHC
Legame di antigeni Si No
solubili
Coinvolgimento di Non necessario Necessita presentazione
molecole MHC dell’antigene
Natura chimica Proteine, lipidi, Principalmente proteine,
degli antigeni polisaccaridi a volte lipidi presentati da
molecole MHC-simili
Proprieta’ Accessibile Peptidi interni lineari
dell’ epitopo aa sequenziali e prodotti dalla processazione
non sequenziali dell’antigene
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Confronto fra il riconoscimento dell’antigene effettuato
dal linfocita B e dal linfocita T
Caratteristiche Linfocita B Linfocita T
Interazione con Processo binario Processo ternario
l’antigene tra Ig ed Ag tra TCR, Ag, MHC
Legame di antigeni Si No
solubili
Coinvolgimento di Non necessario Necessita presentazione
molecole MHC dell’antigene
Natura chimica Proteine, lipidi, Principalmente proteine
degli antigeni polisaccaridi a volte lipidi presentati da
molecole MHC-simili
Proprieta’ Accessibile Peptidi interni lineari
dell’ epitopo aa sequenziali e prodotti dalla processazione
non sequenziali dell’antigene
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Subsets di linfociti T
Citotossici (CD8)
Helper (CD4)
HLA class I-ristretti
HLA class II-ristretti
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HLA di classe I e’ espresso su tutte le cellule
HLA di classe II e’ espresso costitutivamente sulle
cellule presentanti l’antigene “professionali”
(APC = Antigen Presenting Cells)
Dopo attivazione alcune cellule possono esprimere bassi livelli
di HLA II (fibroblasti, glia, linfociti T ed NK, endotelio)
Espressione delle molecole di MHC
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Cellule presentanti l’antigene (APC) (professionali)
Dendritic cell Macrophage B cell
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Confronto fra il riconoscimento dell’antigene effettuato
dal linfocita B e dal linfocita T
Caratteristiche Linfocita B Linfocita T
Interazione con Processo binario Processo ternario
l’antigene tra Ig ed Ag tra TCR, Ag, MHC
Legame di antigeni Si No
solubili
Coinvolgimento di Non necessario Necessita presentazione
molecole MHC dell’antigene
Natura chimica Proteine, lipidi, Principalmente proteine
degli antigeni polisaccaridi a volte lipidi presentati da
molecole MHC-simili
Proprieta’ Accessibile Peptidi interni lineari
dell’ epitopo aa sequenziali e prodotti dalla processazione
non sequenziali dell’antigene
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Processazione dell’antigene
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Le proteine devono essere ubiquitinate per essere digerite dal proteasoma
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Processazione dell’antigene
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La via di processazione per le proteine endogene: il proteasoma
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Il complesso MHC/peptide si forma nel Reticolo Endoplasmatico Rugoso
La via di processazione per le proteine endogene
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Processazione dell’antigene
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La via di processazione per le proteine esogene
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La via di processazione per gli antigeni esogeni
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Processazione dell’antigene
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Le due vie di processazione dell’antigene
Antigeni endogeni
Antigeni esogeni
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Confronto fra il riconoscimento dell’antigene effettuato
dal linfocita B e dal linfocita T
Caratteristiche Linfocita B Linfocita T
Interazione con Processo binario Processo ternario
l’antigene tra Ig ed Ag tra TCR, Ag, MHC
Legame di antigeni Si No
solubili
Coinvolgimento di Non necessario Necessita presentazione
molecole MHC dell’antigene
Natura chimica Proteine, lipidi, Principalmente proteine
degli antigeni polisaccaridi a volte lipidi presentati da
molecole MHC-simili
Proprieta’ Accessibile Peptidi interni lineari
dell’ epitopo aa sequenziali e prodotti dalla processazione
non sequenziali dell’antigene
![Page 27: Antigen processing and presentation...Yoshinori Ohsumi "for his discovery of mechanisms for autophagy" The Nobel Prize in Physiology or Medicine 2016 Nobel-Prize-Medal In yeast (left](https://reader033.fdocuments.in/reader033/viewer/2022050406/5f83b52b33700a6340287724/html5/thumbnails/27.jpg)
Processazione dell’antigene e presentazione
mediante molecole MHC-simili
NKT cells
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Cellule presentanti l’antigene (APC) (professionali)
Dendritic cell Macrophage B cell
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To
Ralph M. Steinman
"for his discovery of the dendritic cell and its role in adaptive immunity".
The Nobel Prize in Physiology or Medicine 2011
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IFN alpha
TNF
IL-1
DC PRECURSOR
IMMATURE DC
MATURE DC
GM-CSF
IL-3
IL-4
Viruses
pathogens, e.g. LPS, bacterial DNA
cytokines, e.g. TNF, GM-CSF
T cells, e.g.CD40L
viral dsRNA
Cellule NK
ANTIGEN PRESENTATION
ANTIGEN CAPTURE
High intracellular MHC II
Endocytosis
Phagocytosis
High CCR1, CCR5, CCR6
Low CCR7
Low CD54, 58, 80, 86
Low CD40
Low CD83, No DC-LAMP
High surface MHC II
Low endocytosis
Low phagocytosis
Low CCR1, CCR5, CCR6
High CCR7
High CD54, 58, 80, 86
High CD40
High CD83, high DC-LAMP, high p55
CYTOKINE RELEASE
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Élie Metchnikoff (1845–1916)
The Nobel Prize in Physiology or Medicine 1908
For his discovery of Phagocytosis (Messina 1882)
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Gli antigeni devono raggiungere gli organi linfoidi secondari
per attivare l’immunita’ acquisita
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Struttura di un linfonodo
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Immunofluorescenza
per cellule dendritiche
(Anti-DEC205)
Immunofluorescenza
per macrofagi
(Anti-DC-SIGN)
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Chemokine Receptors on Dendritic Cells
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DCs travel to lymph nodes
via afferent lymphatic vessels
Peripheral Tissues
Lymphatic circulation
Secondary Lymphoid Organs
Adapted from Janeway and Travers
Veiled cells
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Analyzing DCs in human afferent lymph: a complex task
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The surgical removal of axillary nodes corresponds to a physical interruption of
lymphatic vessels draining lymph from interstitial spaces: as a result, afferent lymph
accumulates.
Axillary nodes dissection induce an accumulation of serous fluids
named “seroma”
Montalto et al, IMLET 2010
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BloodSeroma
Seroma can be considered as an accumulation of afferent lymph
Montalto et al. IMLET, 2010
Barbara Morandi
Characterization of afferent lymph
dendritic cells in humans
Blood
Seroma
CCR7
CD
3
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FSC-A
SSC
-A
0 200 400 600 800 1000
0
200
400
600
800
1000
HLA-DR bright
HLA-DRdim
T
HLA-DR
bright
HLA-DRdim T
HLA-DRdim
10 0 10 1 10 2 10 3 10 4
10 0
10 1
10 2
103
10 4
HL
A-D
R
CD14
0 200 400 600 800 1000
FSC-A
0
200
400
600
800
1000
SS
C-A
10 0 10 1 10 2 10 3 10 4
10 0
10 1
10 2
10 3
10 4
LineageHL
A-D
R
HLA-DRbright
HLA-DRdim
10 0 10 1 10 2 10 3 10 4
0
20
40
60
80
100
% o
f M
ax
Langherin10 0 10 1 10 2 10 3 10 4
10 0
10 1
10 2
10 3
10 4
HL
A-D
R
CD1a
CD1a
LC
Identification of DCs in human afferent lymph from seroma
fluids.
(CD3, CD19,
Nkp46 and
BDCA-2)
Morandi et al. J.Immunol. 2013
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Phenotype of afferent lymph DC subsets
Costimulatory receptors and DC markers
HLA-DRbrightCD14neg DCs displayed a mature phenotype, as they expressed significant
higher levels of costimulatory molecules and DC hallmarks such as DEC205
HLA-DRdim HLA-DRbright
CD80
CD83
CD86
CD40
DEC205
DC SIGN
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Phenotype of afferent lymph DC subsets
Inhibitory receptors and inflammatory chemokine receptors
HLA-DRdim HLA-DRbright
PDL1
PDL2
CCR1
CCR5
CCR7
Morandi et al. J.Immunol. 2013
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20 4
751HL
A-D
R
CD14
88 2
91HL
A-D
R
CD14
Clinical
status
Surgery Post-surgical
tissue
inflammation
Healed tissue
Time from
SurgeryDay 0 Day 7 Day 49
Drained
DCs
Not
available
HLA-DRbrightCD1a+ DCs continuously migrate
from peripheral tissues to secondary lymphoid organs in steady state
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Lavoro seroma
P.Parham
The Immune System
EdiSES, 4°ed., 2015
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Immunoproteasome subunits are similarly expressed
in both DC subsets of human afferent lymph
Morandi et al. J.Immunol. 2013
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Morandi et al. J.Immunol. 2013
Afferent lymph DCs spontaneously release TGFb and induce T regs
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Processazione dell’antigene
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Apoptotic (or necrotic)
cells in peripheral tissues
DC migration to
draining lymph node
Mature DC stimulate
Virus/tumor-specific CTLs
Il fenomeno del “Cross-priming”:
un eccezione delle cellule dendritiche alle vie classiche di presentazione
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Cross-dressing vs Cross-presentation
Campana et al IMLET, 2015
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Cross-dressing occurs via different mechanisms
of MHC transfer
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Plasmacytoid DCs can present exogenous antigens via cross-dressing
Bonaccorsi et al. J.Immunol. 2014
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Bonaccorsi et al. J.Immunol. 2014
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Processazione dell’antigene
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As the autophagosome forms, it engulfs cellular contents, such as damaged proteins
and organelles. Finally, it fuses with the lysosome, where the contents are degraded
into smaller constituents. This process provides the cell with nutrients and building
blocks for renewal.
Autophagy
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To
Yoshinori Ohsumi
"for his discovery of mechanisms for autophagy"
The Nobel Prize in Physiology or Medicine 2016
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In yeast (left panel) a large compartment called the vacuole corresponds to the
lysosome in mammalian cells. Ohsumi generated yeast lacking vacuolar degradation
enzymes. When these yeast cells were starved, autophagosomes rapidly accumulated
in the vacuole (middle panel). His experiments identified 15 genes that are essential for
autophagy.
Ohsumi studies
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Autophagosome formation
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Regulation of intra- and extracellular antigen processing
for MHC class II presentation by macroautophagy
Munz C., Front. Immunol. 2012
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Summary
Antigen processing and presentation are essential for the
development of adaptive immune response via activation of T cells.
The system is tightly regulated for an efficient activation of both
Helper and Cytotoxic T cell compartments.
Antigen presentation by DCs continuosly migrating in steady state
from periphery is also critical for the maintenance of peripheral
tolerance
Many dogmatic assumptions are however challenged by a series of
exceptions in antigen processing and presentation:
cross-priming: presentation of exogenous antigens on MHC class I
cross-dressing: acquisition of foreign antigens w/o processing
outcomes of autophagy: presentation of endogenous antigens on
MHC class II