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MIIM30002 - Principles of Immunology > Lecture 24 - Immune Memory > Flashcards

Lecture 24 - Immune Memory Flashcards

1
Q

What did Thucydides say about Immune memory in ‘History of the Peloponnesian War’

A

“Only those who had recovered from the plague could nerse the sick because they could not catch the disease a second time … this altered state is specific”

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2
Q

Why is immune memory vital for immunity?

A

Ability to resist infection after previous exposure

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3
Q

Describe what was seen in 18th and 19th century Measles epidemics

A

1781: First measles epidemic
• Entire population suffered disease
• Some survived

1846: Second measles epidemic
• Those who had survived from the previous epidemic did not develop disease
• Those who had not previously exposed got the disease

Immune memory can last this long (65 years)

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4
Q

Describe what was done by Jenner

A

18th century; ‘first vaccination’

Smallpox virus infection → fatal disease
Cowpox virus infection → mild disease

People vaccinated against cowpox virus had cross-reactive protection for the smallpox virus

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5
Q

How did vaccination get its name?

A

Vaccinia: cowpox

Vacca: cow

Since the first vaccination was against cowpox virus

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6
Q

When did WHO officially declare that Smallpox was eradicated?

A

1979

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7
Q

Upon which immunological principle are vaccines based?

Describe this principle

A

Immune memory:

  1. (Macfarlane Burnet’s) Theory of Clonal selection and expansion
  2. Differentiation into effector cells
  3. Contraction into memory cells
  4. Long term immunity
  5. Next time the immunogen is seen, the specific memory cells are activated
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8
Q 
Compare the following in Primary and Immunological Memory responses:
 • Magnitude
 • Kinetics
 • Affinity
 • Isotype
A

Magnitude:
• 1°: normal
• 2°: heightened

Kinetics:
• 1°: slow
• 2°: fast

Affinity:
• 1°: low
• 2°: high

Isotype:
• 1°: IgM > IgG
• 2°: IgG, IgA

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9
Q

What are the components of immunological memory?

How long do each of these components last?

A
  1. Ab
    • Stable titre in blood
    • up to 60 years
    • Long lived plasma cells
  2. Memory T-cells
    • Slow decay
    • Half life 10-15 years
    • Some still present after 30 years

Even without re-exposure, these components remain in the body

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10
Q

Describe the required interactions for long-lived humoral immunity

A

Interaction between T(fh) and B cells in the MZ of the B cell follicle

T(fh) stimulate B cells to form a germinal centre, in which CSR, SHM and formation of memory B cells and long lived plasma cells occurs

Those B cells that don’t go into the germinal centres form plasmablasts that are short lived and don’t make great Ab

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11
Q

Where do memory B cells reside?

A
  • BM
  • LNs
  • Spleen
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12
Q

Where do long lived plasma cells hang out?

A

BM

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13
Q

How are newborns protected from infection?

A

Maternal antibodies passively delivered to foetus:
• IgG cross the placenta
• IgA present in breast milk

These persist for up to 6 months

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14
Q

What is the mechanism of protection in most clinically effective vaccines?

What are some exceptions?
What is required for control of these pathogens?

A

Antibody mediated humoral immunity

Some pathogens escape humoral immunity
 • HIV
 • Influenza virus
 • M. tuberculosis
T cell mediated cellular immunity required for control
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15
Q

Compare the following in Primary and Memory responses:
• T cell frequency
• T cell effector activity
• T cell location

A
  1. T cell frequency
    • 1°: Low
    • 2°: Elevated
  2. T cell effector activity
    • 1°: Slow
    • 2°: Fast
  3. T cell distribution
    • 1°: Lymphoid
    • 2°: Lymphoid and peripheral
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16
Q

Describe differentiation of T cells after activation

What are the fates of these cells?

A

Simultaneous generation of both:
• Effector T cells
- perform function
- undergo apoptosis at the end of the immune response

• Memory T cells
- survive and persist

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17
Q

Which receptors do memory T cells express in particular?

Which receptor do they down regulate?

A

Upregulation:
• IL-7R
• IL-15R

Down regulation
• IL-2R

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18
Q

Which cell is required for CD8+ T cell memory formation?

Describe this interaction

A

CD4+ T cells - DC licensing - “ménage-à-trois”

Interaction through DC licensing:

  1. DC stimulates CD4+ T cell (Antigen presentation, co-stimulation, cytokines etc.)
  2. CD40-CD40L interaction between CD4+ T cell and DC
  3. DC is now “Licensed”; expressing specific surface molecules
  4. DC able to stimulate CD8+ T cells to form memory cells

Direct stimulation:
• CD4+ T cell releases IL-2 onto IL-2R on T cell
• (they are in close contact, because they are both interacting with the same DC)

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19
Q

Compare location of:
• Effector Memory T cells
• Central Memory T cells
• Tissue-resident Memory T cells

A
  1. T(EM):
    • Lymphoid organs (BM, LNs, spleen)
    • Blood
  2. T(CM)
    • The periphery (gut, liver, lungs, skin)
    • Blood
  3. T(RM)
    • Epidermis of skin
    • Non-lymphoid tissues (gut, skin, brain, glands, lungs)
    • High numbers only at sites of previous inflammation
    • After inflammation, remain there
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20
Q

Compare surface molecules of memory T-cells, T(EM), with various tissue tropisms

A
  1. Skin tropic
    • CLA
    • CCR4
  2. Gut tropic
    • α4β7
    • CCR9
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21
Q

What is CLA?

On which memory T cells is it found?

A

Cutaneous Leukocyte antigen

It is an E selectin ligand

Found on memory T cells that are Skin-Tropic

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22
Q

What are the two major subsets of memory T cells?

Any recent additions?

A
  • T(CM)
  • T(EM)

• T(RM): tissue-resident memory T cells

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23
Q 
Compare functional properties of T(CM), T(EM) and T(RM):
 • Proliferative potential
 • IL-2
 • Recirculation
 • Effector function
 • Early / late memory
A
  1. Proliferative potential
    • T(CM): great
    • T(EM): low
    • T(RM): low (?)
  2. IL-2 production
    • T(CM): great
    • T(EM): low
    • T(RM): low
  3. Recirculation
    • T(CM): great
    • T(EM): great
    • T(RM): NONE
  4. Effector function
    • T(CM): low
    • T(EM): great
    • T(RM): great
  5. Early / late memory?
    • T(CM): Late
    • T(EM): Early
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24
Q

Compare movement of CD4+ and CD8+ memory T cells in skin

A

CD8+ T cells:
• Epidermis
• Very slow moving, barely moving at all

  1. CD4+ T cells
    • Dermis
    • Much movement
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25
Q

What are T(RM)?
Where specifically are they located?
Where are they never found?

What is their main function?

A

Tissue-resident memory T cells

Located in the epidermis

Cannot circulate in the blood

Main function:
• Immediate local immunity
It takes time for T(EM) to migrate to the infected tissue. T(RM) are already there, and are able to control and contain the infection

26
Q

Compare Primary and Secondary Ab responses

A 
Primary:
 • IgM > IgG
 • Low affinity
 • Low mutation
 • Lower frequency of memory B cells prior to infection
Secondary:
 • IgA, IgG
 • High affinity
 • High mutation
 • More memory B cells prior to infection
27
Q

How do some pathogens escape humoral immunity?

A
  • Rapid antigenic drift

* Intracellular localisation

28
Q

Compare proportion of activated T cells that become Effector and Memory T cells

A

90% : effector T cells

10% : memory T cells

29
Q

Which molecules do terminal effector cell express / not express?

Which T cells are they derived from?

A

Express KLRG1

Derived from T cells that had low expression of IL-7R

30
Q

From which T cells do memory T cells develop?

A

IL-7R(high) precursors

31
Q

Which cytokine are memory T cells dependent?

A

IL-15

32
Q

Describe the experiment that confirmed IL-7R+ cells are memory T cells

A
  1. Infection of mouse
  2. Activated T cells harvested and sorted:
    • IL-7R+
    • IL-7R-
  3. These two cell populations were injected into new mice
    4a. IL-7R- cells in new mice did not survive
    4b. IL-7R+ cells survived in new mice
  4. Re-challenge of infection:
  5. Only IL-7R+ mice could launch a recall response
33
Q

What is IL-15 required for?

A

T cell memory

34
Q

Describe the effect of IL-15 -/- in the mice given the IL-7R+ T cells

A

IL-7R+ : IL-15+/+ : memory response

IL-7R+ : IL-15 -/- : no recall response

Conclusion: T cell memory requires IL-15

35
Q

What is DC licensing?

A

Interaction with CD4+ T cells, resulting in altered surface molecule and cytokine expression, such that they are better able to stimulate CD8+ T cells

36
Q

IL-2 is important for CD8+ T cell stimulation.

Where is this cytokine coming from?

A

CD4+ T cells

both CD4+ and CD8+ interacting on DC

37
Q

What are the marker molecules for Central Memory T cells?

A

CCR7

CD62L

38
Q

Which cells infiltrate the skin upon infection?

A

Both CD4+ and CD8+ T cells can infiltrate

Remember:
Dermis: CD4+ T cells
Epidermis: CD8+ T cells

39
Q

What is the big difference between T(EM) and T(RM)?

A

Tissue-resident Memory T cells cannot circulate in the blood, while T(EM) can

40
Q

What are the signature markers of T(RM)?

A

CD103

CD69

41
Q

Describe the movement of T(RM) within the epidermis

A

Very little movement

Just extend dendrites to look for antigen

42
Q

Why would T(RM) have evolved?

A

Protection of tissues that are not protected by effector or central memory T cells

Such as Herpes

43
Q

Discuss HSV and T(RM)

A
  1. After initial infection, HSV moves up the sensory neurone to the dorsal root ganglion
  2. These cells are latently infected
  3. Every so often, the virus reactivates and causes lesions
    However, this is quite uncommon because:

Tissue resident memory cells

e.g.
Herpes simplex virus
• T(RM) persist at the site of primary infection
• Constant reactivation of the virus, but no infection because of the T(RM) that quash the virus

The rare times when lesions do appear:
• UV exposure / stress etc. depletes the T(RM) cells
• Virus able to cause infection in the epidermis

44
Q

What are plasmablasts?

A

These are short lived plasma cells that form immediately after B cell interaction with T(fh) at the MZ

They are not derived from GC B cells

Thus, they have not undergone CSR and SHM

The Ab is not as good, but provides a rapid initial response

45
Q

Which cytokines do T(fh) release onto B cells to stimulate them?

A

IL-21

46
Q

What is the function of FDCs?

A

Antigen depot

C’ bound antigen binds to CR-½ on FCDs in follicles for recognition by B cells in follicles

47
Q

In the naïve state, where are T cells found?

A

Only in lymphoid organs

Only after the primary response will T cells specific for the antigen be found in the periphery (as well as lymphoid organs).
These are T(EM) cells

48
Q

What is KLRG1?

On which cells is it expressed?

A

Killer cell lectin-like receptor subfamily G1

Terminal effector T cells: KLRG1+
Memory T cells: KLRG1-

NB Terminal effector T cells are derived from cells that express this molecule

49
Q

At which stages do T cells express IL-7R?

A

Naïve T cells

Memory T cells

50
Q

At which stage do T cells express IL-2R?

A

Effector T cells

51
Q

At which stage do T cells express IL-15R?

A

Memory T cells

52
Q

In summary, what are all the things required for T cell memory formation?

A
  • IL-15, IL-15R
  • Derived from IL-7R(high) precursors
  • CD4+ T cell signals (IL-2) / DC licensing
53
Q

Memory T cells expressing E-selectin ligands will be tropic for which organ?

A

Skin

CLA is an E-selectin ligand

54
Q

Which memory T cells express CD62L?

A

Only T(CM) cells

55
Q

Is repeat exposure required for sustained immunity?

A

No

Memory cells last for years in the body and provide protective responses even without frequent re-exposure

56
Q

Which molecules do skin-tropic T(EM) express?

A

CLA

CCR4

57
Q

Which molecules do gut-tropic T(EM) express?

A

α4β7-integrin

CCR9

58
Q

Which memory T cells express CD62L?

A

T(cm)
T(em) are located in the periphery, thus do not express it

T(rm) do not express it

59
Q

What is CD62L?

A

Aka L-selecting

Allows T cell movement into LNs through HEVs

60
Q

What are the surface markers of T(EM)?

Which markers are absent?

A

CCR7-
CCR5+
CD62L-

MIIM30002 - Principles of Immunology (30 decks)

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