Immunology 2 nd Med 2009 Some revision points Con 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 antibody Ingested antigen is presented

Antigen presenting cells - APC Macrophages Dendritic cells B cells Dendritic cell

B cell identification B cells have a specific receptor for antigen antibody molecule

B cell identification B cells have a specific receptor for antigen antigen can bind directly to this receptor

T cell identification T cells have a specific receptor for 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 constant region

TCR - alpha, beta chains The shape of the variable region binds to the shape of different antigens. 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 APC T cytx TARGET CELL CD8 CD8+ T cells interact with antigen bound to MHC class I The 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 APC T cytx TARGET 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 II with peptide T h CD4

CD4+ T cells - MHC II interaction APC T 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 II with peptide

MHC class II on B cells MHC II with 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 constant region

T cell receptor structure Alberts et al.

TCR - gamma, delta chains gamma chain delta chain 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 Alberts et 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 APC T h IL-1 IL-2 CD28 B7

Cytokine product of cells APC T h IL-1 IL-2 Cells interact through the production and release of cytokines - these bind to cells and affect their function CD28 B7

Cytokine products of cells APC T h IL-1 IL-2 Receptors - 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 APC T h IL-1 produced by APC

T cell co-stimulation Essential to T cell activation, division and replication

CD4+ T cells - activation requires 2 signals APC T 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 APC T 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 APC T h IL-2 CD28 B7

CTLA-4 - negative signal APC T 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 APC T h cytokines

CD4+ T cells interact with APC and other cells by releasing cytokines. APC also release cytokines. APC T 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 all involved in B cell stimulation and Ig production

Lymph node - cartoon Alberts et al.

Lymph node - histology Lymphoid follicles

Interferon gamma helps kill intracellular infections MO T h TB Interferon - gamma IFN-  IFN-  activates macrophage killing mechanisms

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 APC T cytx TARGET CELL CD8 perforin enzymes

T cytotoxic cell - recognition of antigen, role of CD8 APC T 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 APC T cytx Target cell virus Lytic granules perforin Enzymes, water, salts Granules - content perforin, 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 antigenic stimuli 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