Adaptive immunity II

Question 1

What happens to T cells in the thymus?

Answer 1

• Undergo early developmental processes to generate T cells expressional clonal TCR (T cell receptor)

Question 2

What are CD4 and CD8?

Answer 2

• Glycoproteins
• Serve as a co-receptor for T cell receptors

Question 3

What does CD4 TCR do?

Answer 3

• Recognises MHC II/peptide complex
• Forms a bridge between the CD4 on TCR and MHC II/peptide complex

Question 4

What does CD8 TCR do?

Answer 4

• Recognises MHC I/peptide complex
• Forms a ‘bridge’ between the CD8 on TCR and MHC I/peptide complex

Question 5

What does the MHC I present?

Answer 5

• Endogenous antigen

Question 6

What does the MHC II present?

Answer 6

• Exogenous antigen

Question 7

How do T cells recirculate and become activated? What 3 signals activate naive T cells?

Answer 7

Recirculation - mechanism by which T cells pass through peripheral sites to find antigens, returning via the lymphatics back into circulation until they find the antigen that activates them

Resting naive T cells activated by integration of 3 signals:

• Antigen recognition
• Co-stimulation
• Cytokines

Question 8

Where are naive T cells activated?

Answer 8

• Secondary lymphoid organs (spleen etc)
• Naive T cells circulate through lymph nodes finding antigens that will activate them

Question 9

What lymphocytes are APCs?

Answer 9

• B lymphocytes
• Macrophages
• Dendritic cell

Question 10

What are the main roles of CTL cells?

Answer 10

• CTL (Cytotoxic T lymphocyte) T cells express CD8
• Kills cells infected with microbes
• Kill tumour cells

Question 11

How are MHCs formed?

Answer 11

MHC molecules are made by antigen presenting cells (APCs)

APCs process antigens into peptides (for most T cells), these ARE the MHC proteins

Peptides bind to MHC molecules

Peptide/MHC complexes presented on APC surface = activation of T cells for specific antigenic peptide

Question 12

How do T cells recognise antigens?

Answer 12

• TCR in T cell recognises antigen presented in context of MHC:
• CD4 TCR recognises antigens displayed by MHC II/peptide complex
• CD8 TCR recognises antigens displayed by MHC I/ peptide complex

Question 13

How are antigens recognised by other immune cells?

Answer 13

• Immunoglobulins on B cells and T cell receptors on T cells recognise any microbial structure
• Distinguish between antigens on different and same microbes
• Self-non-self discrimination can fail = autoimmune disease
• B cells recognise antigens (soluble or cell bound) directly but T cells can’t

Question 14

Describe MHC class I and its structure

Answer 14

• Present in all nucleate cells (including professional APCs)
• Continuous sampling of peptides from within the cells (cytosol) - endogenous antigens
• For this reason MHC I tends to present viral antigens
• Recognised by CD8+ CTL

Structure:
- Ternary complexes of the soluble serum protein beta 2-microglobulin, MHC heavy chain, and bond peptide
- The first 2 domains (alpha 1 and alpha 2) of the heavy chain create the peptide binding left and the surface that contacts the T-cell receptor
- The alpha 3 domain interacts with the CD8 co-receptor of T cells, holds MHC I molecule in place

Question 15

Describe MHC class II and its structure

Answer 15

• Present on professional APCs only (e.g. mononuclear phagocytes, dendritic cells)
• APCs engulf and break up pathogens from outside the cell, presents broken-up peptides on MHC class II from intracellular vesicles
• For this reason MHC II tends to present bacterial antigens
• Recognised by CD4+ Th cells

Structure:
- Heterodimers composed of an alpha and a beta chain
- Both the alpha and beta chain are made up of 2 domains , alpha 1 and 2 and beta 1 and 2
- The alpha 1 and beta 1 domains create the peptide binding cleft

Question 16

Describe the structure of the T cell receptor

Answer 16

• 2 polypeptide chains together forming one antigen binding region linked by disulphide bonds
• 95% of TCRs are composed of an alpha + beta chain (variable domain at top, constant domain at bottom)
• 5% composed of gamma and delta chains

Question 17

How do antibodies work?

Answer 17

Bind to extracellular microbes and toxins and:

• Neutralise microbes (prevent binding of antigen to receptors/cells, blocking entry and its effects on cells)
• Eliminate microbes through opsonisation (increases phagocytosis) and complement activation (opsonisation and lysis of microbe)

Question 18

What does cell mediated immunity fight?

Answer 18

Intracellular microbes:
- Intracellular bacteria in phagosomes of phagocytes
- Viruses in cytoplasm in phagocytes of non-phagocytotic cells
- Parasite = both intra + extracellular

Question 19

What do T cell receptors recognise?

Answer 19

Residues from MHC and residues from the peptide

Question 20

What do delta-gamma T cells recognise?

Answer 20

Antigens not displaced by MHC I and MHC II (are not MHC restricted)

Question 21

What is an endogenous pathogen?

Answer 21

• An infection caused by an infectious agent that is present on or in the host prior to the start of the infection

Question 22

What is an exogenous pathogen?

Answer 22

• Occur when a pathogen enters a patient’s body from their environment

Question 23

How are endogenous pathogens processed and presented to CD8+ cells?

Answer 23

• Virus free in cytosol replicates its viral proteins
• Viral proteins undergo ubiquination (tagged with ubiquitin)
• This targets it to be degraded by proteasome breaking down the proteins into peptides in cytosol (hence endogenous)
• Peptides transported into ER where they’re further broken down to fit better in MHC I
• Assembly of MHC I-peptide complex in ER
• MHC I-peptide complex transported to membrane and presented - recognised by CD8+ T cells

Question 24

How are exogenous pathogens processed and presented by CD4+ cells?

Answer 24

• Uptake of extracellular proteins into vesicular components of antigen presenting cell
• Processing of internalised proteins in endosomal/lysosomal vesicles
• Biosynthesis and transport of MHC II molecules other than endosomes
• Association of processed peptides with class II MHC molecules in vesicles
• Expression of peptide- MHC complexes on cell surface, binds to CD4+ Th cell

Question 25

What is the role of dendritic cells?

Answer 25

- Sentinel cells on skin, mucosa + tissues which capture microbes, phagocytose, and process pathogens and present antigens to T cells - Also increase expression of co-stimulation = tells T cells about infection, they can migrate to naive T cells in lymph nodes and find the specific T cell that needs to be activated

Question 26

Outline the 3 signals for different types of T cell activation

Answer 26

- To activate T cells = MHC presents antigen to T cell receptor (TCR) - For naive T cells = Signal 2, co-stimulation through co-stimulating molecule (CD80//CD86) on APC interact with CD28 on T cell - This will strengthen the bond between the antigen and T cell - 3rd signal is cytokines - APC secretes cytokines to signal T cell

Question 27

Describe the main types of T cell mediated responses and a summary of their roles

Answer 27

- Th1 (CD4+) - help phagocytose kill ingested microbes - Th2 (CD4+) - help eosinophils/mast cells kill helminths - Th17 (CD4+) - defence against bacteria + fungi - CTL (CD8+) - kill cells infected by microbes that grow in cytosol Regulatory T cells (CD4+, CD25+, FOXP3+) - inhibit immune response

Question 28

What is the main cytokine of Th1?

Answer 28

Main cytokine = IFNγ

Question 29

What are the main roles of Th1?

Answer 29

- Activate phagocytes (macrophages) = increased destruction of intracellular pathogens - Does this by secreting cytokine - Stimulate production of IgG Abs = increased phagocytosis of microbes

Question 30

What are some Th1 -mediated diseases?

Answer 30

- Granulomas - Autoimmune diseases

Question 31

How does Th1 induce macrophage activation if microbes block phagocytosis?

Answer 31

Microbes such as salmonella and mycobacterium may block phagocytosis, so they persist in phagosomes, Th1 hep signals occur to induce macrophage activation: - Contact mediated signals CD40L - CD40 - Soluble signals IFN-γ CD40L - CD40 ensures only infected macrophage receive help from Th1 cells = prevent autoimmune responses and inflammation (specificity)

Question 32

Describe the results of Th1 mediated macrophage activation

Answer 32

- Increased ROS (reactive oxygen species) and NO (nitric oxide) - Increased lysosomal enzymes = increased killing of phagocytose microbes - Secretion of cytokines TNF-a, IL-1, IL-12 = local inflammation, increased neutrophils and monocytes recruitment = increased phagocytosis - Tissue repair - PDGF (fibroblast proliferation), TGF-b (collagen synthesis), FGF (angiogenesis)

Question 33

What is the main role of Th2?

Answer 33

- Response against infections with helminths, too large to phagocytose and resistant to microbicidal activities of macrophages

Question 34

How does Th2 help B cells?

Answer 34

Help B cells produce antibodies which: - Opsonise helminths - Activate eosinophils/mast cells which destroy helminths

Question 35

Outline the cytokines important to Th2 and their roles

Answer 35

- IL-4 and IL-13 stimulate IgE production which opsonises helminths - Eosinophils have IgE receptors which bind to Fc region -IL-5 activates bound eosinophils = kill helminths and release granule content : MBP, MCP = can destroy tough integument of worms - IgE opsonises helminths, mast cells bind to Fc of IgE = degranulation of mast cells - release vasoactive amines, TNF-a, lipid mediators > local inflammation = destroy parasite

Question 36

Outline the cytokines important to Th17

Answer 36

- IL 17- chemokine production = neutrophil production, also production of anti-microbial substances (defensins) - IL 22 - increased barrier function of epithelia - IL-17F

Question 37

Where are Th17 normally found?

Answer 37

- Present predominantly in mucosa (GI tract) and defence against intestinal infections by recruiting neutrophils to site of infection

Question 38

How does Th17 respond against infection?

Answer 38

Th17 responses against extracellular bacteria and fungi mainly by promoting neutrophil-mediated inflammation

Question 39

How does Th17 collaborate with Th1?

Answer 39

IN phagocyte-mediated CMI-Th17 recruit neutrophils and monocytes to site, Th1 cells activate phagocytes

Question 40

What are some of the suppression mechanisms Treg use?

Answer 40

Treg = regulatory T cells, regulate immune response, prevents overreaction - Maintain immune tolerance by suppressing immune responses - Identified by expression of CD4 and high levels of CD25 and transcription factor FOXD3 - Inhibit effector CD4+ T cells, CD8+ T cells and antigen presenting cells, B cells Suppression mechanism: - Production of anti-inflammatory cytokines (IL-10, TGF- beta) - Other mechanisms (dependent on contact with Treg-target cells)

Question 41

What are some CD8+ CTL-mediated immune responses?

Answer 41

Eliminate intracellular microbes in cytosol by killing infected cells Important in tumours and organ rejection in transplants Killing = antigen specific and contact dependent so healthy/uninfected cells not killed CTL delivers lethal hit, detaches and target will die - release of cytolytic proteins stored in secretory granules which trigger apoptosis in target cell Cytolytic proteins: - Perforin = form pores = delivery of granzymes - Granzymes A, B and C = initiate apoptosis by activating caspases (granzyme B triggers mitochondrial apoptotic pathway) - Delivered at site of contact = don't kill neighbouring healthy cells Also kill by different method: - FasL on CTL ligates Fas receptor on target cell = activate caspase