Transcript 4 antigenpresentation

THE MOST IMPORTANT FEATURES OF CYTOKINES
 The most important mediators of indirect cell communication in the
immune system („hormones” of the immune system).
 Act in low concentrations.
Cytokines can affect in an autocrine way, in a paracrine way,
or in an endocrine way 
pleiotropic effect.
 Cytokines can act by synergistic or antagonistic ways to each other.
A given cell may by affected by many cytokines resulting in the
same effect  redundant effect.
-
The responsiveness of the given cell is based on the expression of
cytokine-specific receptors.
!
Innate immunity as a first line of defence
Innate immune cells recognize frequently found
structures of pathogens,
these are not found in human cells!
Examples: duple strain RNA
bacterial cell wall components
bacterial flagellin….
Recognition is inevitable
!!
Danger signal!
!!
The innate immune system also recognizes molecules that are released from
damaged or necrotic cells. Such molecules are called damage-associated molecular
patterns (DAMPs).
Specificity of innate immunity
(
)
!
direct connetion
between innate cells
and pathogen
Few receptors (20-30) are responsible for the recognition of all the pathogens
INNATE IMMUNITY II
Effector functions, elimination of pathogens
1. Phagocytosis
2. Killing with soluble mediators
3. Complement system
4. NK cell activation
!!
Monocite /
macrofage
PRR
DC
PRR
Mast
cell
PRR
Granulocites
NK cell
PRR
Absence of
MHCI
Phagocy
tosis
Pathogen
and cell
killing
Recogni
-tion
B
cell
T cell
Complement
Cell-cel
(APC)
Communi
cation
Soluble
Phagocyto
sis
effector
function
Killing
with
solubl
e
mediat
ors
Killing
with
solu
ble
medi
ators
Pathogen
Killing
Monocita/
makrofág
DC
APC
APC
Hízó
Sejt
Granu
locita
NK sejt B-sejt
Felis
merés
kommu
nikáció
Effektor
funkció
APC
T-sejt
Komp
lement
!
!
T helper cells (TH cells) assist other white blood
cells in immunologic processes
Cytotoxic T cells (TC cells, or CTLs) destroy
virally infected cells and tumor cells
Proteins are composed primarily of
polypeptides
(and often non-polypeptide cofactors. )
Peptides are short chains of amino acid
monomers linked by peptide (amide) bonds.
ANTIGEN RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS
THAT EXPRESS MHC MOLECULES
!!
T
II
soluble Ag
Native
membrane Ag
Cell surface MHCpeptide complex
Peptide
antigen
Cell surface
peptides
APC
APC
APC
No T-cell response
T-cell response
Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid
organs, and present foreign antigens to naive T cells.
How can detect the immune system the intracellular
pathogens?
PRR
Antigen presentation
Display intracellular peptides on the surface of cells
MHC
Major histocompatibility comlex
cell surface molecules mediate interactions of T cells with antigen presenting cells
MHCI
Expressed by all nucleated cells
STRUCTURE OF CLASS I MHC MOLECULES
PEPTIDE
2
3
1
2m
!
!
MHCII
!
!
Expressed by professional antigen presenting cells
Macrophage, dendritic cell, B cell
STRUCTURE OF CLASS II MHC MOLECULES
PEPTIDE
1
1
2
2
MEMBRANE RECEPTORS
Intracellular peptide binding
capacity
One binding site can
accomodate multiple peptides
Cleft geometry
-chain
-chain
Peptide
2-M
MHC class I accommodate
peptides of 8-10 amino acids
Peptide
-chain
MHC class II accommodate
peptides of >13 amino acids
CYTOSOL-DERIVED PEPTIDES ARE
PRESENTED BY MHC-I FOR T-CELLS
RECOGNITION OF EXOGENOUS AND ENDOGENOUS
ANTIGENES BY T-LYMPHOCYTES
!
!
Tc
Th
TCR
TCR
Peptide
Peptide
MHCI
MHCII
Exogenous Ag
Endogenous
Ag
APC
Peptides of endogenous proteins
(virus, tumor) bind to class I MHC
molecules presented to cytotoxic
T cells
Peptides of exogenous proteins
(toxin, bacteria, allergen) bind to class
II MHC molecules presented to helper
T cells
MHC RESTRICTION
T-sejt
T-sejt
TCR
TCR
M HC
MHC
MHC
APC
APC
APC
!
T-sejt
TCR
One single T-cell receptor can recognize a given MHC – peptid complex
The TCR-specific peptide is recognized only when its presented with an MHC on
which the TCR had been selected during its development in the thymus
If the peptide binds to another MHC molecule no T-cell recognition occurs (by this
T cell)
If the same MHC molecule binds another peptide, no T-cell recognition occurs
!!
T cell receptor (TCR) recognizes peptide antigen and
simultaneously
also recognizes the MHC molecule that is displaying that peptide
Specificity of innate immunity
Specificity of T cells
Tc
Distinct T cell
receptors
Peptides derived
from different microbes
peptid
Tc
MHC
APC
APC
!
Specificity of innate immunity
(
!
direct connetion
between innate cells
and pathogen
)
Specificity of T cells
T
Distinct T cell
receptors
peptid
Peptides derived
from different microbes
APC
T
MHC
APC
No direct
connetion
between T cell
and pathogen
APC-T cell
connection
A given type of MHC is able to bind different peptides
Does not distinguish self and nonself peptides
!
B cell epitop
T cell epitop
B cells recognize:
T cells recognize:
proteins
polysaccharides
lipids
DNS
steroids
drugs, etc
peptides (8-23 amino acid)
Tissue or soluble antigens
!
!
only when these peptides are
presented by MHC molecules
on APC cells
!!
MHCI
Displays intracellular antigens
to cytotoxic T cells
ER is the site of protein synthesis
MHC molecules are also synthetised in ER
Degradation of
endogenous proteins
takes place in the
proteasomes, they are
presented on MHC I
Transporters associated with
antigen processing (TAP1 & 2)
Hydrophobic
transmembrane
domain
Lumen of ER
Peptide
ER membrane
Cytosol
Peptide
Peptide
Peptide antigens
from proteasome
ATP-binding cassette
(ABC) domain
Transporter has preference for longer than 8 amino acid peptides
with hydrophobic C termini.
Degradation of endogenous proteins in
(immune) proteasomes
TAP: Transporter associated
with antigen processing
!!
MHCII
Displays extracellular antigens
to helper T cells
Professional phagocytic cells
macrophages
neutrophyl granulocytes
dendrtitic cells
!!
the phagocytosed cells or molecules may modify
the functions of the cell
phagocytosis followed by enzymatic degradation
Professional antigen presenting cells
macrophages
B lymphocytes
dendrtitic cells
they express MHCII molecules
the protein degradation products (peptides) can be presented
to T lymphocytes by MHC molecules
!!
1 Recognition
2. Uptake
3. Peptide production
4. MHCII-peptide complex
5. Presentation
Pathogen recognition by innate immune system
1. Directly via PRR
2. Indirectly via opsonization
1 Recognition
2. Uptake
Phagocytosis
3. Peptide production
!
Invariant chain (Ii) function:
1. Chaperon – Conformation
2. Blocking of the peptide binding
3. Transport of MHC complex
Comparision of intracellular events of MHCI and MHCII pathways
T cell recognition
Peptide fragments
Peptides associate to MHC
Antigen prezenting cell
Expression of peptide/MHC complex on the cell surface
Recognition of peptide/MHC complex by TCR
T cell
RECOGNITION OF EXOGENOUS AND ENDOGENOUS
ANTIGENES BY T-LYMPHOCYTES
!
!
Tc
Th
TCR
TCR
Peptide
Peptide
MHCI
MHCII
Exogenous Ag
Endogenous
Ag
APC
Peptides of endogenous proteins
(virus, tumor) bind to class I MHC
molecules presented to cytotoxic
T cells
Peptides of exogenous proteins
(toxin, bacteria, allergen) bind to class
II MHC molecules presented to helper
T cells