Libro consigliato: Immunobiology, Janeway 6th edizione

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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 defensenot specificno immunologic memory (does not getstronger with more exposures)

Innate or Natural Immunity

• Mechanisms include– Mucous barriers– Natural killer cells– Polymorphonuclear and mononuclear

phagocytic cells

Macrophage

Neutrophil

Phagocytosis of Bacteria by Macrophages and Neutrophils- First Line of Defense

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

• Two types: helper T cells (CD4)cytotoxic T cells

(CD8)

• Generally eliminate intracellular pathogens

• Involved with humoral immunity

• Secrete antibodies

• 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

CD4 or CD8

co-receptor

TCR

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 antigen-

presenting 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

Activation and secretion of cytokines

CD4

Stabilises the MHC antigen complex

TCR

MHC II/antigen

Processing of microbial fragments onto MHC class II by

macrophage

Interaction between CD8+ T cells and antigen/MHC I complexes

CD8+ T cell kills the infected cell

CD8

Stabilises the MHC antigen complex

TCRMHC I/antigen

Virus infects a cell

T Cell Development (I)- Thymus

T Cell Development (II)- Periphery

Features of the Adaptive Immune Responses

DescriptionMechanismFeature

Non-reactivity to self-antigens or non-pathogenic

antigens

Central: negative selection (T, B)

Peripheral: angergy (T, B)

(T) AICD, suppression

Tolerance

Acceleration of elimination of specific pathogens

Proliferation of antigen-specific T or B cells ligation with APCs

Clonal Expansion

Recall of immune response is rapid and larger

Differentiation of naïve to effector cells

Memory

Lymphocyte repertoire is extremely large

DNA rearrangement in TCR and BCR genes

Diversity

Immune responses are specific for distinct antigens

DNA rearrangement in TCR and BCR genes

Specificity

EffectorAg elimination

MemoryMemory maintenance

RecognitionAg presentation

ActivationDifferentiation

NaïveT/B

Activated T/B

Humoral& Cellular Immunity

MemoryT/B

Different Phases of Adaptive Immune Response

Modified from Cell. Mol. Immunol. 5th ed. Abbas et al.

Days after antigen exposure

0 7 14 >30

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Antigen challenge

Clonal Expansion

ApoptosisHomeostasis

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 TCells 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 expressionRed: Inducible expression

Activation of Naïve T Cells Requires Two IndependentSignals- 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

CD8

IL-2

1. CTL differentiation without Th cells

CD8

4-1BBL4-1BB

IL-2

3. Th cells enhance APCs to stimulate CTL differentiation

Modified from Cell. Mol. Immunol. 5th ed. Abbas et al.

CD8IL-2

2. Th cells produce cyto- kines to stimulate CTL differentiation

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

Genes Dev. 2000 14:1693

Factors Involved in the Differentiation of Helper T Cells

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.