Immunol mol med 2

Conleth Feighery

2010

This lecture …..

• Importance of lymphocytes in immune system

• Identification of T and B cells

• How these cells bind antigen - receptors

• How cells become activated

• The involvement of MHC molecules in T cell function

Medical journals

• It is never too early to start …. dipping into journals

2 you might consider -

• New England Journal of Medicine

• Lancet

Major cells of the immune system

T cell

B cell

lymphocytes

neutrophil

monocyte

dendritic cell

2 types of lymphocytes

T

B

Mature in thymus - regulate, kill

Mature in the bursa - antibody

Neutrophils

ingest foreign materialdigest it

“phagocytosis”

• Neutrophils most numerous white cell in circulation

• Short lived - 1 day

• Non-specific

Monocytes

Macrophage in tissue“present” antigen

monocyte

Phagocytic cells5 % of circulating cells

Macrophage

Dendritic cells

T cell- help- suppress- kill

B cell

antibodyIngested antigen is

presented

Major antigen presenting cell in tissues

Monocytes / macrophages

T cell- help- suppress- kill

B cell

antibodyIngested antigen is

presented

Antigen presenting cells - APC

• Dendritic cells

• Macrophages

• B cells

B cell identification

B cells have a specific receptor

for antigen

antibody molecule

B cell identification

B cells have a specific receptor

for antigen

antibody receptorbinds antigen directly

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 shape of different antigens.

variable region

variable region

constant region

B cell receptor

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

Variable region

Variable region

constant

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 via TCR

• Need antigen to be “presented” APC

• Antigen has to be bound to “MHC” mols.

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

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.…”

MHC class I on target cell

APC

MHC I molecule

TARGETCELL

peptide

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 cells

All 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

T cell stimulation

• T cells bind to antigen and MHC

• Need to bind to a second molecule for full stimulation

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

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

CD4+ T cells - MHC II interaction

cytokines

APCT h

CD4

CD28 B7

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

cytokines

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

APCT h

CD4

CD28 B7

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 !