4th LECTUREPublic Health BSc

CONNECTING INNATE AND ADAPTIVE IMMUNITY:

ANTIGEN PRESENTATIONArpad Lanyi

MECHANISM OF DEFENSE IN GENERAL

• environmental changes (e.g. infection)

• recognition (by receptors)

• effector functions (e.g. to get rid of pathogens)

SENSINGRECOGNITION

SIGNALING

RESPONSE

INNATE IMMUNITY

CellsReceptors

Signaling pathwaysCell-Cell

collaboration

Effector functions

DEFENSE SYSTEMS

ADAPTIVE IMMUNITY

SENSINGRECOGNITION

SIGNALING

RESPONSE

EFFECTOR MECHANISMS OF INNATE IMMUNITY

NATURAL KILLER CELLS

PHAGOCYTIC CELLS

COMPLEMENT SYSTEM

PHAGOCYTIC SYSTEMNEUTROPHIL - MACROPHAGE - DENDRITIC CELL

Defense against infectious diseases

Elimination of tumor cellsTransplantation rejection

Gatekeeper functionSensing commensals and pathogensRapid activation of innate immunityPriming adaptive immune responsesMaintenance of self-tolerance

Infections Trauma Physical and Chemical agents (thermal injury, irradiation, chemicals) Tissue Necrosis Foreign bodies (splinters, dirt, sutures) Hypersensitivity or autoimmune reactions

Increased vascular diameter increased flood flow

Increased vascular permeability edema

Migration of leukocytes from the blood to the affected tissue

(diapedesis/extravasation), accumulation, effector functions

MAJOR COMPONENTS OF INFLAMMATION:

TRIGGERS OF ACUTE INFLAMMATION:

ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE

activating surfaceenzyme

Activating surface required!

inactive precursors limited

proteolysis

COMPLEMENT SYSTEM

THE EFFECTOR FUNCTIONS OF THE COMPLEMENT SYSTEM

1. help inflammatory processes:– increase vascular permeability– recruit leukocytes

2. opsonize pathogens facilitate recognition by innate immune cells

3. direct lysis of pathogens/cells (Membrane Attack Complex – MAC)

SECONDARY LYMPHOID ORGANS/TISSUES

• LYMPH NODES

• SPLEEN

• TONSILS (Waldeyer’s ring)

• Diffuse lymphoid layers under the

epithelial barriers:

– SALT (skin-associated lymphoid

tissue)

– MALT (mucosa-associated lymphoid

tissue)• BALT (bronchus-associated lymphoid tissue)

• GALT (gut-associated lymphoid tissue)

Sites of lymphocyte activation and terminal differentiation

THE MEETING OF INNATE AND ADAPTIVE CELLS

ACTIVATION OF T CELLS

T cells can only recognise antigens that are bound to MHC molecules!

THE OUTCOME OF INFECTION IN A POPULATION WITH POLYMORPHIC MHC GENES

MHC-Gen

vv

vv

vv

v

vv

v

v

v

v

v v v

v

vv

v

vv

v

vv

Example: If MHC X was the only type of MHC molecule

Population threatenedwith extinction

Pathogen that evades MHC

X

MHCXX

Population is protected

MHCI

Displays intracellular antigensto cytotoxic T cells

Peptides of endogenous proteins bind to class I MHC molecules presented to cytotoxic T cells

Tc

Endogenous Ag

RECOGNITION OF ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES

TCR

Peptide

MHCI

APC

MHCI is expressed by all nucleated

cells

STRUCTURE OF CLASS I MHC MOLECULES

A polymorphic α chain and and a non-polymorph β2 mikroglobulin

α1 és α2 domains are responsible for peptide binding

MHC class I accommodatepeptides of 8-10 amino acids

Cleft geometry

MHC class II accommodatepeptides of >13 amino acids

b2-M

a-chain

Peptide

a-chain

b-chainPeptide

• Synthesized antigens – endogenous antigens (virus, tumor)• Internalized antigens – exogenous antigens (any protein)

• Degrade protein antigens to peptides = processing• Protein-derived peptides are presented by MHC (HLA) membrane

proteins antigen presentation

• MHC molecules present both self and non-self protein-derived peptides

• MHC class I molecules are expressed in all nucleated cells• MHC class II molecules are expressed by professional antigen

presenting cells

ANTIGEN PRESENTING CELLS

CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS

Degradation of endogenous proteins takes place in the proteasomes, they are presented on cell surface by

MHC I

MHC do not recognize or distinguish self and nonself peptides

Antigen presentation goes in the absence of pathogen or T cells as well

!

System optimalization 2:

MHCI present the intracellular area. Next step, how could the MHC molecules (and the T cells)

monitor the extracellular enviroment?

a2

a1

b2

b1

PEPTIDE

STRUCTURE OF CLASS II MHC MOLECULES

MHCII

Expressed by professional antigen presenting cellsMacrophage, dendritic cell, B cell

a2

a1

b2

b1

PEPTID PEPTIDE

α1 and β1 domens are responsible for peptide binding

A polymorphic α and a polymorphic β chain

STRUCTURE OF CLASS II MHC MOLECULES

MHC class I accommodatepeptides of 8-10 amino acids

Cleft geometry

MHC class II accommodatepeptides of >13 amino acids

b2-M

a-chain

Peptide

a-chain

b-chainPeptide

Presentation of extracellular peptides by MHCII

Peptides of endogenous proteins (virus, tumor) bind to class I MHC

molecules

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

The recognition of the MHC-presented peptide antigen is not enough for T cell activation!

DIFFERENTIATION OF CD4+ T CELLS• The polarization of helper T cell

response is regulated by multiple factors:– origin of the presented peptide– nature of the APC– microenvironment– etc.

• In case of an infection both Th1 and Th2 cells are generated in different sites of the secondary lymphoid organs

• Imbalance occurs in case of special disorers:– Th1 dominance: e.g.

mycobacterial infection– Th2 dominance: e.g. allergy, SLE

cellular,pro-

inflammatory

humoral,anti-

inflammatory