Lecture 6: Effector Responses of the Immune System

Question 1

Humoral effector responses are mediated by what?

Answer 1

Antibodies

Question 2

Cell-mediated effector responses are mediated by what (give examples)?

Answer 2

innate immune cells (E.g. NK cells, macrophages, neutrophils)
and cells of the adaptive immune system (E.g. cytotoxic T-cells, CD4+ T-helper cells)

Question 3

Give an example of when the humoral and cell-mediated immune responses interact?

Answer 3

When macrophages (cell-mediated) phagocytose antibody-bound pathogens (humoral)

Question 4

What is the aim of effector responses of the immune system?

Answer 4

eliminate pathogens and infected cells
- also clear cells that are damaged or abnormal (E.g. cancerous)

Question 5

What are the antibody-mediated effector functions? (there are 6)

Answer 5

1. neutralise pathogens and toxin (inactivates them and prevents binding to cells)
2. Agglutination (prevents binding to cells and enhances pathogen clearance)
3. Opsonisation to enhance phagocytosis by macrophages
4. Activation of the complement cascade via the classical pathway
5. Antibody-dependent cell-mediated cytotoxicity (ADCC) to promote NK cell-induced apoptosis
6. Degranulation (bind to extracellular parasites, granulocytes recognise Fc region and triggers degranulation)

Question 6

What differs between antibody isotypes?

Answer 6

the Fc region

Question 7

How do different antibody isotypes produce different effector functions?

Answer 7

they have different Fc regions and depending on which Fc receptor they bind, this can produce different effects.

Question 8

Which antibody isotype is the first produced during infection?

Answer 8

IgM (pentamer)

Question 9

What are IgE antibodies mostly produced against?

Answer 9

worm infections
allergy

Question 10

Where are IgA antibodies typically produced?

Answer 10

at mucosal sites

Question 11

Which antibody is abundant in the blood?

Answer 11

IgG

Question 12

What are Fc receptors (FcR)?

Answer 12

have extracellular immunoglobulin domains that recognise the Fc domains of antibodies and intracellular signalling domains
- different FcRs recognise different antibody subtypes
- different cells express different sets of FcRs to fit their effector purpose.

Question 13

Which FcR is largely expressed on eosinophils, mast cells and basophils?

Answer 13

FcƐRI

Question 14

Which FcR is largely expressed on macrophages, dendritic cells and granulocytes?

Answer 14

FcγR

Question 15

Which antibody isotypes are involved in neutralisation?

Answer 15

IgA or IgG

Question 16

How does antibody neutralisation affect viruses and bacteria?

Answer 16

Viruses = antibody binding to surface can prevent cell entry

Bacteria = antibodies can bind toxins making them harmless

Question 17

How does antibody opsonisation effector function works?

Answer 17

• IgG and IgA antibodies surround pathogen
• The Fc regions can bind to FcRs on macrophages
• this induces phagocytosis (digestion of pathogens in phagolysosome)

Question 18

Explain how antibodies can fix complement as an effector function of an immune response?

Answer 18

IgG and/or IgM are recognised by the C1 complement complex leading to activation of the classical complement pathway
- this induces opsonisation by C3b and phagocytosis (via CR1 receptor)
- induces lysis of the pathogen or the infected cell via the Membrane Attack Complex (MAC)

Question 19

Explain how antibodies can promote antibody-dependent cell-mediated cytotoxicity (ADCC) as an effector function of an immune response?

Answer 19

IgG binds to peptides on surface of infected cell
Fc region recognised by FcγRIIIα on NK cells
this causes the NK cell to degranulate (releasing perforins and granzymes) and induce apoptosis in the target cell

Question 20

Explain how antibodies can induce activation of granulocytes as an effector function of an immune response?

Answer 20

IgE antibodies bound to parasites (worms) or allergens are recognised by the FcεR expressed by mast cells, eosinophils and basophils
- this induces the release of histamine and other vasoactive inflammatory mediators that promote the release of polarising cytokines that induce Type 2 T-helper cell production

Question 21

What are the cytotoxic effector cells of the cell-mediated innate and adaptive immune responses?

Answer 21

Innate: NK cells
Adaptive: CD8+ cytotoxic T-lymphocytes (CTLs)
(And natural killer T-cells (NKT cells) which have innate and adaptive features)

Question 22

How do cytotoxic cells induce cell dealth?

Answer 22

apoptosis

Question 23

What are the two ways in which cytotoxic T-cells can be activated?

Answer 23

1. Sequential activation
2. Simultaneous activation

Question 24

Describe the sequential activation of CTLs?

Answer 24

• licensing of an antigen presenting cell (APC) via PRR by pathogen or CD40 by TH1 cells
• once activated, these APCs can produce cytokines such as IL-12
• licensed APC interacts with naive CD8+ T-cell via MHCI, TCR and CD80/86-CD28 co-receptor
• third signal from IL-2 in environment required for full activation and differentiation into CTL.

Question 25

Describe the simultaneous activation of CTLs

Answer 25

- simultaneous interaction of an APC with an activated TH1 cell and naive CD8+ T-cell causes APC licensing and CD8+ T-cell activation at the same time - efficient as the third signal of IL-2 comes directly from the TH1 cell to promote CTL differentiation.

Question 26

Describe the action of CTLs

Answer 26

1. CTL forms immunological synapse with a target cell 2. secretory granules move along microtubules towards the synapse 3. secretory granules fuse with the presynaptic membrane 4. perforin monomers assemble in target cell membrane to make pores through which granzyme serine proteases can pass - these cleave proteins in target cell and results in apoptosis of the target cell

Question 27

Which cells secrete perforins and granzymes?

Answer 27

CTLs and NK cells

Question 28

What are natural killer T-cells (NKT cells)?

Answer 28

a type of T-lymphocyte that have some properties similar to NK cells - have invariant TCR - TCR recognises certain glycolipids presented by CD1d (a non-classical MHC molecule) - act as both helper cells and cytotoxic cells - include CD4+ and CD4- populations - lack some classical T-cell markers (such as CD3) - express some NK cell markers (such as NK1.1)

Question 29

True or false: NKT cells, similarly to other T-cells, express very variant TCRs?

Answer 29

False: they express an invariant TCR (specific alpha and beta chains present on almost all NKT cells)

Question 30

What are two ways in which NK cells can be activated?

Answer 30

By binding via Fc receptors to antibodies bound to surface antigens of tumour cells or virally infected cells or by binding via activating NK cell receptors (presence of activating signal and absence of inhibitory signal can result in NK cell activation)

Question 31

Why do lymphocytes circulate between the blood, spleen and lymph nodes?

Answer 31

To sample antigens presented by antigen presenting cells

Question 32

How long do lymphocytes spend in each lymph node before returning into the circulation?

Answer 32

12-18 hours

Question 33

Describe the recirculation of lymphocytes

Answer 33

Lymphocytes move from tissues into the lymph fluid, through different lymph nodes. Drain from lymph fluid back into the blood stream. Some immune cells get recruited back into the tissues where they are re-circulated

Question 34

True or false: naive lymphocytes are not particularly motie?

Answer 34

False: they are highly motile and enter lymph nodes via HEVs

Question 35

Upon entering the lymph nodes, what do B cells do in the follicles?

Answer 35

Browse antigens presented by the follicular dendritic cell network

Question 36

Upon entering the lymph nodes, what do T cells do in the paracortex?

Answer 36

Interact with fibroblast reticular cell networks (stromal cells that support the migration of T-cells through lymph to locate antigens to which they can respond to)

Question 37

What occurs during days 1-2 of an infection?

Answer 37

- innate immune cells bind pathogens (PRRs bind PAMPS, release inflammatory signals including cytokines and chemokines) - neutrophils first cell at site of inflammatory response (surround pathogens and phagocytose) - NK cells and macrophages eliminate pathogen before further infection occurs - chemokines produced attract APCs (including DCs) which take antigens from site of infection and present in nearby antigens to initiate adaptive immune cells

Question 38

True or False: B-cells recognise processed antigens (peptide antigens bound to MHC)?

Answer 38

False: B cells recognise unprocessed antigens that enter the lymph nodes via the afferent lymphatics (it is T-cells that recognise processed antigens - antigen peptides bound to MHC)

Question 39

What occurs during days 1-5 of an infection in terms of the adaptive immune response?

Answer 39

Following APC activation, they move to the lymph nodes - T cell and APCs interact in the paracortex T-cell zone causing T-cell proliferation and differentiation into effector cells Antigens enter lymph nodes (small soluble ones, larger ones via SCSMs) and recognised by B-cells - migrate to T-cell zone for full activation - form primary foci - enter into germinal centre (edit BCR to increase affinity to antigen) Fully activated T and B-cells leave lymph nodes and recruited into site of infection

Question 40

What occurs during from day 5 onwards of an infection in terms in the peripheral tissues?

Answer 40

Fully activated T and B-cells leave lymph nodes and recruited into site of infection (effector and memory cells) - effector lymphocytes express chemokine homing receptors that allow them to follow chemokine gradients produced by inflammation (immune cells, endothelium) - also have receptors (such as selectins, LFA that can interact with molecules expressed by inflamed vascular endothelium, such as ICAM-1) - once in the peripheral tissue, antibodies and CTLs help eliminate pathogens from site of infection - memory cells remain at site in case of re-infection