the most important mediators of indirect cell communication in the immune system („hormones” of...
DESCRIPTION
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). !!TRANSCRIPT
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.
THE MOST IMPORTANT FEATURES OF CYTOKINESTHE MOST IMPORTANT FEATURES OF CYTOKINES
!
Recognition is inevitableRecognition is inevitable
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….
!!
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).
!!
direct connetion between innate cells
and pathogen)(
Specificity of innate immunity
Few receptors (20-30) are responsible for the recognition of all the pathogens
!
INNATE IMMUNITY II
Effector functions, elimination of pathogens
1. Phagocytosis2. Killing with soluble mediators
3. Complement system4. NK cell activation
!!
Monocite / Monocite / macrofage macrofage DCDC Mast Mast
cellcellGranulo-Granulo-
citescites NK cellNK cell B B cellcell T cellT cell Comple-Comple-
mentment
Recogni-tion
PRR PRR PRR PRR Absen-ce ofMHCI
Cell-cel(APC)
Communication
Soluble
effector function
Phagocytosis
Killing with soluble mediators
Phagocytosis
Killing with soluble
mediators
Pathogen and cell killing
Pathogen Killing
Monocita/makrofág
DC HízóSejt
Granulocita
NK sejt B-sejt T-sejt Komplement
Felismerés
kommunikáció
APC APC APC
Effektor funkció
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 REQUIRESPEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS
THAT EXPRESS MHC MOLECULES
IIT
No T-cell response
soluble Ag
Native membrane Ag
Peptide antigen
Cell surface MHC-peptide complex
T-cell response
Cell surfacepeptides APC
!!
APCAPC
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 presentationDisplay intracellular peptides on the surface of cells
MHC
Major histocompatibility comlex
cell surface molecules mediate interactions of T cells with antigen presenting cells
PEPTIDE
1
3
2
2m
STRUCTURE OF CLASS I MHC MOLECULES
MHCI
Expressed by all nucleated cells
!!
2
1
2
1
PEPTIDE
STRUCTURE OF CLASS II MHC MOLECULES
MHCII
Expressed by professional antigen presenting cellsMacrophage, dendritic cell, B cell
!!
MEMBRANE RECEPTORSMEMBRANE RECEPTORS
Intracellular peptide binding Intracellular peptide binding capacitycapacity
One binding site can One binding site can accomodate multiple peptidesaccomodate multiple peptides
MHC class I accommodatepeptides of 8-10 amino acids
Cleft geometry
MHC class II accommodatepeptides of >13 amino acids
-M
-chain
Peptide
-chain
-chainPeptide
CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS
Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic
T cells
Tc
Endogenous Ag
RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES
Exogenous Ag
Th
Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper
T cells
TCR
Peptide
MHCI
TCR
Peptide
MHCII
APC
!!
T-sejt
TCR
APC
MHC
T-sejt T-sejt
TCR TCR
APC
MHC
APC
MHC
MHC RESTRICTION
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
APC
Tc
APC
peptid
MHCPeptides derivedfrom different microbes
Distinct T cell receptors
!
direct connetion between innate cells
and pathogen
No direct connetion
between T cell and pathogen
APC-T cell connection
APC
T
APC
peptid
MHC
T
Peptides derivedfrom different microbes
Distinct T cell receptors
)(
Specificity of innate immunity
Specificity of T cells
!
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:
proteinspolysaccharideslipidsDNSsteroidsdrugs, etc
Tissue or soluble antigens
T cells recognize:
peptides (8-23 amino acid)
only when these peptides are presented by MHC molecules on APC cells
!!
MHCI
Displays intracellular antigensto 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
ER membrane
Lumen of ER
Cytosol
Transporters associated withantigen processing (TAP1 & 2)
Transporter has preference for longer than 8 amino acid peptideswith hydrophobic C termini.
TAP-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTAP-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTAP-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTAP-1 TAP-2
Peptide
TAP-1 TAP-2
PeptideTAP-1 TAP-2
Peptide
TAP-1 TAP-2
Peptide
ER membrane
Lumen of ER
Cytosol
TAP-1 TAP-2
Peptide
ATP-binding cassette(ABC) domain
Hydrophobictransmembranedomain
Peptide antigensfrom proteasome
Degradation of endogenous proteins in (immune) proteasomes
TAP: Transporter associatedwith antigen processing
MHCII
Displays extracellular antigensto helper T cells
!!
Professional phagocytic cellsmacrophagesneutrophyl granulocytesdendrtitic cells
the phagocytosed cells or molecules may modify the functions of the cell
phagocytosis followed by enzymatic degradation
Professional antigen presenting cellsmacrophagesB lymphocytesdendrtitic 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
Phagocytosis2. Uptake
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
Expression of peptide/MHC complex on the cell surface
Recognition of peptide/MHC complex by TCR
Antigen prezenting cell
T cell
Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic
T cells
Tc
Endogenous Ag
RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES
Exogenous Ag
Th
Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper
T cells
TCR
Peptide
MHCI
TCR
Peptide
MHCII
APC
!!