Lecture 15 - Integrated Dynamics of Innate and Adaptive Immunity

Question 1

Innate vs adaptive immunity: how are they encoded, what receptors do they use, what are their advantages, and what are their disadvantages?

Answer 1

Innate:
* Encoded in the germline (inherited)
* PRRs - DAMPs, PAMPs, MAMPs
* Quick to act, may control pathogen itself
* Weaker than adaptive immune response - pathogen may go out of control and the innate immune system struggles to control it

Adaptive:
* Somatically generated (gene rearrangement)
* BCRs and TCRs
* Strong immune response that may generate memory and therefore immunity
* Takes a while to generate, makes wasteful generated cells while making the correct cells, and has the potential for autoimmunity

Question 2

Adaptive immune system: why is it so slow?

Answer 2

Require time for:
* Priming
* Clonal expansion
* Polarisation
* Recruitment

Question 3

Immune defence timeline: how do both the innate and adaptive immune systems develop?

Answer 3

Immune response starts as an Antigen (Ag)-independent response (innate) and remains active and involved during the response

With time the adaptive immune response becomes more focused:
* Type of pathogen (bacteria/fungi/worm)
* Specific pathogen (Ag-dependent responses develop)

Question 4

The four stages of immune defence

Answer 4

STAGE 1 - Barrier Breach
STAGE 2 - Activation of Innate Immunity
STAGE 3 - Lymphatic Spread
STAGE 4 - Adaptive Immune Response

Question 5

Barrier breach: what stage of the immune defence is it, how easy is it to occur, and what does the immune system do?

Answer 5

The first stage

Not as straightforward as it sounds, the invader must:
* Adhere, penetrate, or colonize the tissue it has invaded then replicate itself in its new environment

MAMPs and DAMPs released

Question 6

Activation of Innate Immunity: what stage of the immune defence is it, what does the immune system do, and what are the key features of this stage?

Answer 6

Stage 2

Innate immune cells are activated:
* Tissue-resident macrophages
* Tissue-resident Dendritic cells
* Epithelial cells
(Cytokines produced cause activation of:)
* ILCs
* TCRγδ+ T cells

• Production of cytokines and chemokines
• Endothelium becomes leaky - allowing for recruitment into the tissue
• Endothelial cells express integrins and other molecules which allow circulating immune cell recruitment
• Activation time is very rapid, occurring within minutes of the infection
• This innate immune response is sustained for several days
• Largely non-specific (Although cytokines made by ILCs (for example) will start to tailor the response)
• A lot of pathogens can be controlled at this stage

Question 7

Lymphatic spread: what stage of the immune defence is it, what does the immune system do, and what are the key features of this stage?

Answer 7

Stage 3

Adaptive immunity is triggered when the infection eludes the local innate responses OR a threshold of antigen is met

• DCs and macrophages take antigens to the local lymph nodes
• T/B-cells become activated and differentiate/proliferate

Question 8

Adaptive immune response: what stage of the immune defence is it, what does the immune system do, and what are the key features of this stage?

Answer 8

Stage 4

• Ag-specific T cells and antibodies enter the site of infection
• Due to Ag-specificity these responses are more powerful than those in the early stages as they allow precise targeting of the pathogen
• Facilitate immunity

Question 9

Type 1 cell immune response: what is it, what cells are included, and what effector functions are there?

Answer 9

Immune response targeted to intracellular infection

• Th1 cells
• ILC1

Activation of macrophages, monocytes, production of cytokines good against intracellular pathogens (IgG1/IgG2)

Question 10

Type 2 cell immune response: what is it, what cells are included, and what effector functions are there?

Answer 10

Immune response targeted to extracellular infection

• Th2 cells
• ILC2

Activation of macrophages, eosinophils, mast cells, and production of cytokines good against extracellular pathogens (IgE)

Question 11

Type 3 cell immune response: what is it, what cells are included, and what effector functions are there?

Answer 11

Immune response targeted to fungal infection

• Th17 cells
• ILC3

Activation of neutrophils and production of cytokines good against fungal pathogens (opsonising IgG)

Question 12

ILC1: what is it, what does it do, and what is its transcription factor?

Answer 12

Innate lymphoid cell 1

• Produce IFN-γ and TNF-α in the early stages of infection
• Help coordinate activation of Th1 cells and IgG1 and IgG2 (fighting intracellular pathogens)
• Potentiates the activation of macrophages and monocytes

t-bet

Question 13

ILC2: what is it, what does it do, and what is its transcription factor?

Answer 13

Innate lymphoid cell 2

• Help coordinate activation of Th2 cells and
  IgE
• Potentiates the activation of eosinophils, Mast Cells, and Macrophages

GATA3

Question 14

ILC3: what is it, what does it do, and what is its transcription factor?

Answer 14

Innate lymphoid cell 3

• Help coordinate activation of Th17 cells and opsonising IgG production
• Potentiates the activation of neutrophils

RORα/γt

Question 15

Chemokine receptors: why are they required, what are some examples, and in what cells are they expressed?

Answer 15

T-cells need to leave lymph nodes and arrive at the correct tissue to deal with infections - they become attracted to chemokines which bring them where they are needed

• CXCR3 - expressed on Th1 cells
• CRTH2 - expressed on Th2 cells
• CCR4 - expressed on Th2 cells
• CCR5 - expressed on Th1 cells and monocytes
• CCR6 - expressed on Th17 cells
• CCR7 - trafficking to lymph nodes
• P-selectin glycoprotein ligand 1 - Binds P/E selecting, expressed on activated epithelium
• S1PR1 - allows trafficking out of the lymph nodes to the blood

Question 16

Chemokines: what do they do and what are they produced by?

Answer 16

Attract leukocytes expressing the correct receptor for the produced chemokine

Question 17

Th1 cells: what are they, what do they do in tissues, and what does this result in?

Answer 17

Th1 cells - part of the type 1 response in dealing with intracellular infections

• Promote classical activation of macrophages by supplying CD40L and IFNγ, causing development into M1 macrophages
• Promotes monocyte generation - Th1 cells make IL-3 and GM-CSF – stimulates monocyte production in the bone marrow (eventually results in more M1 macrophages)
• Promotes monocyte recruitment - Th1 cells make TNFα and LTα which change the surface properties of endothelial cells allowing monocytes to adhere to them and induce CCL2 at inflammatory sites which directly recruits monocytes

Question 18

M1 macrophages: what are they, what immune response are they involved in, and what do they do?

Answer 18

Classically activated macrophages that are promoted to support the type 1 immune response

• Exhibit enhanced abilities to kill intracellular pathogens
• Expressing high levels of CD80/86 and CD40 (expressing signal 1/2 better to T-cells)
• Secrete IL-12 which acts on ILC1/Th1 cells to increase IFNγ production which promotes stabilisation of Th1 cells and promotes naïve CD8+ T cells to become CTLs

Question 19

Th2 cells: what are they, what do they do in tissues, and what does this result in?

Answer 19

Th2 cells - part of the type 2 response in dealing with extracellular infections

• Secrete IL-5 which recruits and activates eosinophils which produce Major Basic Protein (MBP) which directly kills parasites and they also produce parasite-specific Igs, mediating ADCC
• Secrete IL-13 which promotes epithelial cell repair and mucus and smooth muscle movement which makes the environment less hospitable for pathogens
• Promote alternative activation of macrophages, causing development into M2 macrophages

Question 20

M2 macrophages: what are they, what immune response are they involved in, and what do they do?

Answer 20

Alternatively activated macrophages that are promoted to support the type 2 immune response

• Promote wound healing
• Proliferate in response to IL-4 (no need for monocyte generation and recruitment, they themselves can proliferate)
• Express arginase I - catalyses the breakdown of arginine to ornithine and proline (ornithine promotes tissue remodelling and repair)

Question 21

Th17 cells: what are they, what do they do in tissues, and what does this result in?

Answer 21

Th17 cells - part of the type 3 response in dealing with fungal infections

• Secrete IL-17A/F which acts on epithelial cells and stromal cells, which causes them to secrete CXCL2/8 which recruit neutrophils
• Promotes monocyte generation - promotes epithelial cells to produce GM-CSF - stimulates monocyte production in the bone marrow
• Produces IL-22, driving epithelial cells to produce antimicrobial peptides - RegIIIβ and RegIIIγ (can directly kill bacteria), S100A8 and S100A9 (sequester Zinc and Manganese from bacteria)
• IL-22 also promotes epithelial cell proliferation, promoting shedding of epithelial cells and making colonisation more difficult

Question 22

Innate and adaptive immune systems: are they independent, separate mechanisms?

Answer 22

No, they produce effects and activate each other in a loop fashion to increase the effect of the response to cause a larger, stronger immune response

Question 23

CD4+ T-cells: can they act independently of TCR stimulation?

Answer 23

Not normally - they can once at site of infection after becoming activated and fully differentiated they can produce cytokines following stimulation with specific pairs of cytokines (one STAT TF and one NFκB activating cytokine):
* Th1 - produce IFNγ after IL-12/IL-18 stimulation
* Th2 - produce IL-5/IL-13 after TSLP/IL-33 stimulation
* Th17 - produce IL-17/IL-22 after IL-1/IL-23 stimulation

Question 24

Resolution of inflammatory responses: what happens?

Answer 24

• Antigens that initiated the response are removed
• In the absence of antigen, most effector T-cells undergo death by neglect - apoptosis due to loss of survival factors such as IL-2 which is secreted in response to Ag-encounter - as antigen is depleted, IL-2 levels drop
• Apoptotic lymphocytes are cleared by phagocytes - they recognise the membrane lipid phosphatidylserine which is displayed in the inner membrane on healthy cells and the outer membrane on apoptotic cells
• Both pathogen and pathogen-specific effector cells are removed, excluding developed memory cells