the most important mediators of indirect cell communication in the immune system („hormones” of...

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

!!