Libro consigliato:
Immunobiology, Janeway 6th edizione
Esame orale
Date appelli:
30 Maggio ore 9.30
14 giugno
4 luglio
13 settembre
16 novembre
14 dicembre
Immune System Function
• Defends the body against the outside world
– Microorganisms
• Defends the body against the inside world
– Abnormal cells
• Functions by modulation
– Highly complex up and down regulatory mechanisms
Types of Immunity
Two major types
Innate immunity or natural immunity
Acquired immunity or specific immunity
Self Recognition Concept
• Immune system must recognize what is part
of the body and what is not part of the body
– Different classes of histocompatibility complex
proteins
• Important in immune stimulation
Innate immunity
first front line of defense
not specific
no immunologic memory (does not get
stronger with more exposures)
Innate or Natural Immunity
• Mechanisms include
– Mucous barriers
– Natural killer cells
– Polymorphonuclear and mononuclear
phagocytic cells
Phagocytosis of Bacteria by Macrophages and
Neutrophils- First Line of Defense
Neutrophil
Macrophage
Listeria
Acquired Immunity
• It is specific and generally increases with exposure
to foreign substances
• Two kinds of acquired immune response
– Humoral immunity
• Immunoglobulins
– Protein called antibody and substances that react with antibodies
are called antigens
– Cell-mediated immunity
• Specialized cells that destroy foreign target cells
Immunogen
• Immunogen is a substance that triggers an
immune response. These include:
– Proteins
– Polysaccharides
– Nucleic acids
Overview of Immune
Mechanisms
Recognition of Self
• Genetic variations in specific proteins
– Class I and Class II major histocompatibility
complex (MHC)
– Immune system develops with a concept of self
Cell Types
•
•
•
•
Polymorphonuclear phagocytes
Mononuclear phagocytes
Lymphocytes
Antigen presenting cells
Lymphocytes
• Cells with large nucleus and small amount
of cytoplasm
– Circulate in the blood and lymph systems
• Develop from pluripotent stem cells as the
lymphoid series
Blood Cell
Two Major Types of Lymphocytes
• T-cells
– develop in the thymus
• B-Cells
T-Lymphocytes
• T-lymphocytes
– Initiating an immune response
– Modulating an immune response
• T-lymphocytes have the following cluster
differentiation (CD) or surface proteins
– CD3+
– CD4+
• T-helper cells
– CD8+
• T-suppressor cells
• T-cytotoxic cells
B-Lymphocytes
• Develop and mature in the bone marrow
• Produce class specific Immunoglobulins
Cells of the specific immune
system
T cell
B cell
•Involved with cell mediated immunity
•Involved with humoral immunity
•Two types:
•Secrete antibodies
helper T cells (CD4)
cytotoxic T cells (CD8)
•Generally eliminate
intracellular pathogens
•Generally eliminate
extracellular
pathogens
Immunity mediated by T cells
• T cells recognise and destroy cells infected with foreign
antigen
– e.g. viral infection, intracellular bacteria (mycobacterium
tuberculosis), intracellular parasites)
• T cells can either:
– kill infected cells themselves
• (CD8+ T cells also called cytotoxic T cells)
or
– recruit help to eliminate the infected cell by means of soluble
mediators called cytokines
• (CD4+ T cells also called helper T cells)
How do T cells recognise
specific antigenic epitopes?
CD4 and CD8 are co-receptors
that serve to aid TCR signalling
TCR
CD4 or CD8
co-receptor
CD3 signalling
complex
How does the TCR get to see
specific epitopes derived from
and intracellular foreign
antigen?
i.e. if the infecting agent such as
a virus is within its target cell
how does the T cell get access?
Antigen
Presentation
Professional Antigen Presenting Cells (APCs)
Major Histocompatibility Complex
(MHC)
• Two types
– MHC class I
• Expressed on the surface of all nucleated cells in your
body
– MHC class II
• Expressed on the surface of professional antigenpresenting cells e.g. macrophages and dendritic cells
• CD4+ T cells interact with MHC class II on
antigen-presenting cells
• CD8+ T cells interact with MHC class I
which is expressed on all nucleated cells
within your body
Processing of intracellular
foreign antigen
• Presentation of antigen on MHC class II
molecules, example:
– Macrophages/Dendritic cells phagocytose bacteria
which are digested into small antigen fragments
– These fragments are processed in the cytoplasm and
bound to MHC class II molecules
– Antigen/MHC II complexes are subsequently expressed
on the surface of the antigen-presenting cell
• Presentation of antigen on MHC class I
molecules, example:
– Influenza virus infects a cell and becomes
incorporated into the host DNA where it can
replicate itself
– Each cell in your body constantly screens itself
by processing ‘self’ antigens and binding them
to MHC class I molecules which are
subsequently expressed on the cell surface
– If viral protein is present it to will be processed
and expressed on the cell surface in the context
of MHC class I
Interaction between CD4+ T cells
and antigen/MHC II complexes
MHC
II/antigen
TCR
Processing of
microbial
fragments
onto MHC
class II by
macrophage
CD4
Stabilises the MHC
antigen complex
Activation
and
secretion
of
cytokines
Interaction between CD8+ T cells
and antigen/MHC I complexes
Virus infects a
cell
MHC I/antigen
TCR
CD8
Stabilises the MHC
antigen complex
CD8+ T
cell kills
the
infected
cell
T Cell Development (I)- Thymus
T Cell Development (II)- Periphery
Features of the Adaptive Immune Responses
Feature
Mechanism
Description
Specificity
DNA rearrangement in TCR and
BCR genes
Immune responses are
specific for distinct antigens
Diversity
DNA rearrangement in TCR and
BCR genes
Lymphocyte repertoire is
extremely large
Memory
Differentiation of naïve to effector Recall of immune response
cells
is rapid and larger
Clonal
Expansion
Proliferation of antigen-specific T
or B cells ligation with APCs
Acceleration of elimination
of specific pathogens
Tolerance
Central: negative selection (T, B)
Peripheral: angergy (T, B)
(T) AICD, suppression
Non-reactivity to selfantigens or non-pathogenic
antigens
Different Phases of Adaptive Immune Response
Recognition
Activation
Effector
Memory
Ag presentation
Differentiation
Ag elimination
Memory
maintenance
Clonal
Expansion
Naïve
T/B
0
Activated
T/B
7
Antigen
challenge
Apoptosis
Homeostasis
Humoral
& Cellular
Immunity
14
Memory
T/B
>30
Days after antigen exposure
Modified from Cell. Mol. Immunol. 5th ed. Abbas et al.
Time Course for Induction of Antiviral Response
Where Pathogens Enter the Body
 Skin : DC, macrophages
 Gut : GALT (Gut-Associated Lymphoid Tissue)
 Lung : BALT (Bronchia-Associated Lymphoid Tissue )
 Blood : Spleen/lymph nodes
 Genital duct: MALT (Mucosal-Associated Lymphoid Tissue)
Where T/B Cells Meet Foreign Antigens-Spleen
and Lymph Nodes
Induction and Effector Phases of Cell-mediated Immunity
Cell. Mol. Immunol. 5th ed. Abbas et al.
Requirements for a Professional APC
1. Able to ingest and present antigens
2. Express both MHC I and MHC II
3. Express Co-stimulatory molecules
Molecules Involved in the Interactions of
T Cells and APCs during T Cell Activation
T cell
APC
TCR-CD3 complex
MHC-peptides
CD4/CD8 (coreceptor)
MHC I/II
Adhesion molecules
Ligands
Costimulatory molecule
Ligands
Adhesion Molecules involved in the Interactions of T
Cells with APCs
Costimulatory Molecules of T Cells and APCs
T cell
APC
CD28, CTLA-4
B7.1 B7.2
ICOS
LICOS
4-1BB ( on CD8)
4-1BBL
PD-1
PD-L
Blue: Constitutive expression
Red: Inducible expression
Activation of Naïve T Cells Requires Two Independent
Signals- TCR + Costimulatory Signals
Mechanism of Peripheral Tolerance- TCR Ligation
Without Costimulatory Molecules
Role of Costimulation and Th Cells in the
Differentiation of CD8 T Cells
IL-2
CD8
CD8
IL-2
1. CTL differentiation
without Th cells
CD8
4-1BBL
4-1BB
IL-2
2. Th cells produce cytokines to stimulate CTL
differentiation
3. Th cells enhance
APCs to stimulate
CTL differentiation
Modified from Cell. Mol. Immunol. 5th ed. Abbas et al.
Distribution of Different APCs in Lymph Node
Features of Mature DC
 Increased expression of MHC I and II
 Expression of CCR7 for homing to 2o Lymphoid organs
 Expression of costimulatory molecules B7
 Increased expression of DC-SIGN
 Secret cytokines IL-12 and TNFa
 Secret DC-CK to attract naïve T cells
Dendritic Cells are Immature in Peripheral Tissues and
Become Mature after Taking up Antigens
DC Take up Antigen in the Skin and Migrate to Lymphoid
Organs Where They Present It to T Cells
Involvement of TLR in Linking Innate Immunity
to Adaptive Immunity
Nature Immunology 2001 2:675
Microbial Substances Induce Co-stimulatory
Activity in Macrophages
B Cells Use Ig Receptor to Capture Specific Antigens
Summary of Different Properties of APCs
Naïve T Cells can Differentiate into Three
Effector Cells
FasL
Fas-FasL-mediated Apoptosis Pathway
(Extrinsic Pathway)
Back
Release of Effector Molecules is Localized
on Contact Sites of T and Target Cells
Cytotoxic Effector Proteins Released by T Cells
Perforin of Cytotoxic T Cells Can Insert and
Form Pores in the Membrane of Target Cells
Differentiation of Immature CD4 Helper T Cells
In terms of cytokine
production
Factors Involved in the Differentiation of Helper T Cells
Genes Dev. 2000 14:1693
Cytokine Receptor Families by Their Structures
Functions of Th1 Cytokines
Effector Functions of Th1 Cells
Cell. Mol. Immunol. 5th ed. Abbas et al.
Th1 Cells Activate Macrophages to Become
Highly Microbicidal
Functions of Th2 Cytokines
Effector Functions of Th2 Cells
Cell. Mol. Immunol. 5th ed. Abbas et al.