Immunology 2nd Med 2009

Some revision pointsCon Feighery

Lecture content

• How to recognise T cells and B cells• Structure of the T cell receptor• The different types of T cells• The role of MHC in activation of T cells• How cytokines influence the immune system

Monocytes / macrophages

T cell- help- suppress- kill

B cell

antibodyIngested antigen is

presented

Antigen presenting cells - APC

• Macrophages• Dendritic cells• B cells

Dendritic cell

B cell identification

B cells have a specific receptorfor antigen

antibody molecule

B cell identification

B cells have a specific receptorfor antigen

antigen can bind directlyto this receptor

T cell identification

T cells have a specific receptorfor antigen

TCR = T cell receptor

CD3 on T cells

CD3 molecule bound to TCR

CD3 signals to cell interior

T cell receptor - 2 chains

alpha chain

beta chain

TCR - alpha, beta chains

alpha chain

beta chain

variable region

variable region

constant region

TCR - alpha, beta chains

The shape of the variable region binds to the shape of different antigens.

variable region

variable region

constant region

T helper cells -CD4+ T cells

CD4 molecules on T helper cells

T cytotoxic cells -CD8+ T cells

CD8 molecules on T cytotoxic cells

T cell molecules

• T cell receptor = TCR• CD3 - signaling molecule• CD4 - on T helper cells• CD8 - on T cytotoxic cells

• “CD” = cluster of differentiation - used in describing many molecules of immune system

For T cells to function ….

• Need TCR - binds antigen• Need CD3 - signals binding• Need antigen to be “presented” APC• Antigen has to be bound to “MHC” mols.• Co-stimulation signal to T cell ….

MHC molecules

Major Histocompatability Complex = MHC• 2 types• MHC class I• MHC class II• Enable T cells to react with antigen• MHC = transplantation antigens - also called

HLA molecules = human leucocyte antigens

CD8+ T cells - MHC I interaction

APCT cytxTARGET

CELL

CD8

CD8+ T cells interact with antigen bound to MHC class IThe CD8 molecule binds exclusively to MHC class I

CD8+ T cells can kill target cells by inserting a ‘perforating hole’ in the cell, through which enzymes enter, damaging the cell

APCT cytxTARGET

CELL

CD8

• perforin• enzymes

MHC class I

• Found on all cells in the body• Essential for function of T cytotoxic cells• Viral peptides bind to MHC I

Top end of a MHC class I molecule

Don Wiley, died 2001

I'm sorry, but I just don't understand anything in biology unless I know what it looks like.'

Scientist, crystallographer

Don Wiley - appreciation

"Wiley was a crystallographer: this is the ultimate molecular biology. ...The image of a class I MHC protein with its peptide cargo firmly in place will stand as a landmark Wiley discovery that forever changed the field of immunology.…”

CD4+ T cells - MHC II interaction

APC

MHC IIwith peptide

T h

CD4

CD4+ T cells - MHC II interaction

APCT h

CD4

CD4+ T cells interact with antigen bound to MHC class II molecules

MHC class II

Found on few cells in body -• Macrophages• Dendritic cells• B cellsAll these cells present antigen = antigen

presenting cells or APC

MHC class II on APC

APC

MHC IIwith peptide

MHC class II on B cells

MHC IIwith peptide

B

antibody

B cells act as APC

T h B

antibody

Structure of molecules of IS

• T cell receptor• MHC class I• MHC class II• Antibody molecules

Knowledge of these structures helps understand how the immune system works !

Structure of molecules of IS

• T cell receptor• MHC class I• MHC class II• Antibody molecules

Knowledge of these structures helps understand how the immune system works !

TCR - alpha, beta chains

alpha chain

beta chain

variable region

variable region

constant region

T cell receptor structure

Alberts et al.

TCR - gamma, delta chains

gamma chain

delta chain

variable region

variable region

constant region

Immunoglobulin super-family

Many molecules in the immune system have an Ig-like structure and hence, belong to the “Ig superfamily”.

Alberts et al.

MHC I and II structure

Albertset al.

CYTOKINES

Cells of the immune system ‘talk’ to each other by producing cytokines - like

‘text messages’ informing cells what their function should be!

Cytokine products of cells

APCT h

IL-1

IL-2

CD28 B7

Cytokine product of cells

APCT h

IL-1

IL-2Cells interact through the productionand release of cytokines - these bind to cells and affect their function

CD28 B7

Cytokine products of cells

APCT h

IL-1

IL-2Receptors - cytokines bind to specific cell receptors

Cytokines

• Small protein molecules c. 20,000 aa• Specific types produced by different cells• Bind to cells and affect cell function• Some are called “interleukins” or IL

IL-1 helps T cell activation

APCT h

IL-1 producedby APC

T cell co-stimulation

Essential to T cell activation, division and replication

CD4+ T cells - activation requires 2 signals

APCT h

CD4

T cell receptor binding to antigen = signal 1

CD28 B7

CD28 binds to B7 = signal 2

Activation of T cells

• Requires 2 signals• Signal 1 - TCR, MHC, antigen• Signal 2 - CD28 binding to B7• Both signals must be from the same APC• ONLY now can T cell proliferation start

Stimulated T cell - IL-2 produced

APCT h

CD4

CD28 B7

IL-2

IL-2 receptor

IL-2 binds to receptor on cell - causes cell growth, division

IL-2 required for T cell growth

APCT h

IL-2

CD28 B7

CTLA-4 - negative signal

APCT h

CD4

T cell receptor binding to antigen = signal 1

CTLA-4 B7

CTLA-4 binds to B7 - inhibits stimulation

Bi-directional flow of cytokines

APCT h

cytokines

CD4+ T cells interact with APC and other cells by releasing cytokines. APC also release cytokines.

APCT h

cytokines

The type of cytokines that are released are crucial to the type of immune response which results

T cell cytokines affect B cells

T h B

IL-4,5,6

T cell cytokines affect B cells

T h B

IL-4, IL-5, IL-6

IL-4, 5 and 6 allinvolved in B cellstimulation and Igproduction

Lymph node - cartoon

Alberts et al.

Lymph node - histology

Lymphoid follicles

Interferon gamma helps kill intracellular infections

MOT h

TB

Interferon - gammaIFN-

IFN- activates macrophage killingmechanisms

Cytotoxic T cells

CD8+ T cells can kill target cells by inserting a ‘perforating hole’ in the cell, through which enzymes enter, damaging

the cell

APCT cytxTARGET

CELL

CD8

• perforin• enzymes

T cytotoxic cell - recognition of antigen, role of CD8

APCT cytx

T cytotoxic cell reacting with virus antigen presented by MHC class I molecule

CD8

MHC I

Target cell

virus

T cytotoxic cell - cytolytic mechanism

APCT cytx

Target cell

virusLytic granules

perforinEnzymes, water, salts

Granules - contentperforin,enzymes

Types of T helper cells

• Cytokine production by T helper cells varies• Effect on the immune system varies• Sub-types of T helper cells• Th1 cells – interferon gamma product• Th2 cells – IL-4, IL-5, IL-6• Th17 cells – IL-17• T regulatory cells – IL-10

Effect of antigens on APC

Various antigenicstimuli

Different cytokines

APC

Different surface molecs

APC - effect on T cell response

APC

TH 1

TH 2

T reg

IFN-

IL-4

IL-10

Cytokines and T cells

• Depending on the antigen, APC may produce different sets of cytokines

• These cytokines determine the type of T cell that proliferates

• Different types of T cells produce specific sets of cytokines