Transcript and the T cells - immunology.unideb.hu

4th LECTURE
Public Health BSc
CONNECTING INNATE AND
ADAPTIVE IMMUNITY:
ANTIGEN PRESENTATION
Arpad Lanyi
MECHANISM OF DEFENSE IN GENERAL
• environmental changes (e.g. infection)
• recognition (by receptors)
• effector functions (e.g. to get rid of
pathogens)
DEFENSE SYSTEMS
ADAPTIVE IMMUNITY
INNATE IMMUNITY
SENSING
Cells
SENSING
RECOGNITION
Receptors
RECOGNITION
SIGNALING
Signaling
pathways
SIGNALING
Cell-Cell
collaboration
RESPONSE
Effector
functions
RESPONSE
EFFECTOR MECHANISMS OF INNATE IMMUNITY
NATURAL KILLER CELLS
PHAGOCYTIC CELLS
COMPLEMENT SYSTEM
PHAGOCYTIC SYSTEM
NEUTROPHIL - MACROPHAGE - DENDRITIC CELL
Gatekeeper function
Sensing commensals and pathogens
Rapid activation of innate immunity
Priming adaptive immune responses
Maintenance of self-tolerance
Defense against infectious
diseases
Elimination of tumor cells
Transplantation rejection
TRIGGERS OF ACUTE INFLAMMATION:






Infections
Trauma
Physical and Chemical agents (thermal injury, irradiation, chemicals)
Tissue Necrosis
Foreign bodies (splinters, dirt, sutures)
Hypersensitivity or autoimmune reactions
MAJOR COMPONENTS OF INFLAMMATION:

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
ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE
COMPLEMENT SYSTEM
inactive
precursors
enzyme
limited
proteolysis
activating surface
Activating surface required!
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
Sites of lymphocyte activation and terminal differentiation
•
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)
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
Example: If MHC X was the only type of MHC molecule
MHC-Gen
MHC
XX
v
v
Pathogen that
evades MHC
X
v
Population threatened
with extinction
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
v
Population is protected
MHCI
Displays intracellular antigens
to cytotoxic T cells
RECOGNITION OF ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES
MHCI is expressed
by all nucleated
cells
Tc
TCR
Peptide
MHCI
Endogenous
Ag
APC
Peptides of endogenous proteins
bind to class I MHC molecules
presented to cytotoxic T 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
Cleft geometry
a-chain
a-chain
Peptide
b2-M
MHC class I accommodate
peptides of 8-10 amino acids
Peptide
b-chain
MHC class II accommodate
peptides of >13 amino acids
ANTIGEN PRESENTING CELLS
• 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
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?
MHCII
Expressed by professional antigen presenting cells
Macrophage, dendritic cell, B cell
STRUCTURE OF CLASS II MHC MOLECULES
PEPTIDE
b1
a1
b2
a2
STRUCTURE OF CLASS II MHC MOLECULES
A polymorphic α and a polymorphic β chain
PEPTID
b1
a1
b2
a2
α1 and β1 domens are
responsible for peptide binding
PEPTIDE
Cleft geometry
a-chain
a-chain
Peptide
b2-M
MHC class I accommodate
peptides of 8-10 amino acids
Peptide
b-chain
MHC class II accommodate
peptides of >13 amino acids
Presentation of extracellular peptides by MHCII
RECOGNITION OF EXOGENOUS AND ENDOGENOUS
ANTIGENES BY T-LYMPHOCYTES
Tc
Th
Exogenous Ag
Endogenous
Ag
Peptides of endogenous proteins
(virus, tumor) bind to class I MHC
molecules
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
cellular,
proinflammatory
humoral,
antiinflammatory
•
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