Lecture 24 - Immune Memory Flashcards
What did Thucydides say about Immune memory in ‘History of the Peloponnesian War’
“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”
Why is immune memory vital for immunity?
Ability to resist infection after previous exposure
Describe what was seen in 18th and 19th century Measles epidemics
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)
Describe what was done by Jenner
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
How did vaccination get its name?
Vaccinia: cowpox
Vacca: cow
Since the first vaccination was against cowpox virus
When did WHO officially declare that Smallpox was eradicated?
1979
Upon which immunological principle are vaccines based?
Describe this principle
Immune memory:
- (Macfarlane Burnet’s) Theory of Clonal selection and expansion
- Differentiation into effector cells
- Contraction into memory cells
- Long term immunity
- Next time the immunogen is seen, the specific memory cells are activated
Compare the following in Primary and Immunological Memory responses: • Magnitude • Kinetics • Affinity • Isotype
Magnitude:
• 1°: normal
• 2°: heightened
Kinetics:
• 1°: slow
• 2°: fast
Affinity:
• 1°: low
• 2°: high
Isotype:
• 1°: IgM > IgG
• 2°: IgG, IgA
What are the components of immunological memory?
How long do each of these components last?
- Ab
• Stable titre in blood
• up to 60 years
• Long lived plasma cells - 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
Describe the required interactions for long-lived humoral immunity
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
Where do memory B cells reside?
- BM
- LNs
- Spleen
Where do long lived plasma cells hang out?
BM
How are newborns protected from infection?
Maternal antibodies passively delivered to foetus:
• IgG cross the placenta
• IgA present in breast milk
These persist for up to 6 months
What is the mechanism of protection in most clinically effective vaccines?
What are some exceptions?
What is required for control of these pathogens?
Antibody mediated humoral immunity
Some pathogens escape humoral immunity • HIV • Influenza virus • M. tuberculosis T cell mediated cellular immunity required for control
Compare the following in Primary and Memory responses:
• T cell frequency
• T cell effector activity
• T cell location
- T cell frequency
• 1°: Low
• 2°: Elevated - T cell effector activity
• 1°: Slow
• 2°: Fast - T cell distribution
• 1°: Lymphoid
• 2°: Lymphoid and peripheral
Describe differentiation of T cells after activation
What are the fates of these cells?
Simultaneous generation of both:
• Effector T cells
- perform function
- undergo apoptosis at the end of the immune response
• Memory T cells
- survive and persist
Which receptors do memory T cells express in particular?
Which receptor do they down regulate?
Upregulation:
• IL-7R
• IL-15R
Down regulation
• IL-2R
Which cell is required for CD8+ T cell memory formation?
Describe this interaction
CD4+ T cells - DC licensing - “ménage-à-trois”
Interaction through DC licensing:
- DC stimulates CD4+ T cell (Antigen presentation, co-stimulation, cytokines etc.)
- CD40-CD40L interaction between CD4+ T cell and DC
- DC is now “Licensed”; expressing specific surface molecules
- 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)
Compare location of:
• Effector Memory T cells
• Central Memory T cells
• Tissue-resident Memory T cells
- T(EM):
• Lymphoid organs (BM, LNs, spleen)
• Blood - T(CM)
• The periphery (gut, liver, lungs, skin)
• Blood - 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
Compare surface molecules of memory T-cells, T(EM), with various tissue tropisms
- Skin tropic
• CLA
• CCR4 - Gut tropic
• α4β7
• CCR9
What is CLA?
On which memory T cells is it found?
Cutaneous Leukocyte antigen
It is an E selectin ligand
Found on memory T cells that are Skin-Tropic
What are the two major subsets of memory T cells?
Any recent additions?
- T(CM)
- T(EM)
• T(RM): tissue-resident memory T cells
Compare functional properties of T(CM), T(EM) and T(RM): • Proliferative potential • IL-2 • Recirculation • Effector function • Early / late memory
- Proliferative potential
• T(CM): great
• T(EM): low
• T(RM): low (?) - IL-2 production
• T(CM): great
• T(EM): low
• T(RM): low - Recirculation
• T(CM): great
• T(EM): great
• T(RM): NONE - Effector function
• T(CM): low
• T(EM): great
• T(RM): great - Early / late memory?
• T(CM): Late
• T(EM): Early
Compare movement of CD4+ and CD8+ memory T cells in skin
CD8+ T cells:
• Epidermis
• Very slow moving, barely moving at all
- CD4+ T cells
• Dermis
• Much movement
What are T(RM)?
Where specifically are they located?
Where are they never found?
What is their main function?
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
Compare Primary and Secondary Ab responses
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
How do some pathogens escape humoral immunity?
- Rapid antigenic drift
* Intracellular localisation
Compare proportion of activated T cells that become Effector and Memory T cells
90% : effector T cells
10% : memory T cells
Which molecules do terminal effector cell express / not express?
Which T cells are they derived from?
Express KLRG1
Derived from T cells that had low expression of IL-7R
From which T cells do memory T cells develop?
IL-7R(high) precursors
Which cytokine are memory T cells dependent?
IL-15
Describe the experiment that confirmed IL-7R+ cells are memory T cells
- Infection of mouse
- Activated T cells harvested and sorted:
• IL-7R+
• IL-7R- - 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 - Re-challenge of infection:
- Only IL-7R+ mice could launch a recall response
What is IL-15 required for?
T cell memory
Describe the effect of IL-15 -/- in the mice given the IL-7R+ T cells
IL-7R+ : IL-15+/+ : memory response
IL-7R+ : IL-15 -/- : no recall response
Conclusion: T cell memory requires IL-15
What is DC licensing?
Interaction with CD4+ T cells, resulting in altered surface molecule and cytokine expression, such that they are better able to stimulate CD8+ T cells
IL-2 is important for CD8+ T cell stimulation.
Where is this cytokine coming from?
CD4+ T cells
both CD4+ and CD8+ interacting on DC
What are the marker molecules for Central Memory T cells?
CCR7
CD62L
Which cells infiltrate the skin upon infection?
Both CD4+ and CD8+ T cells can infiltrate
Remember:
Dermis: CD4+ T cells
Epidermis: CD8+ T cells
What is the big difference between T(EM) and T(RM)?
Tissue-resident Memory T cells cannot circulate in the blood, while T(EM) can
What are the signature markers of T(RM)?
CD103
CD69
Describe the movement of T(RM) within the epidermis
Very little movement
Just extend dendrites to look for antigen
Why would T(RM) have evolved?
Protection of tissues that are not protected by effector or central memory T cells
Such as Herpes
Discuss HSV and T(RM)
- After initial infection, HSV moves up the sensory neurone to the dorsal root ganglion
- These cells are latently infected
- 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
What are plasmablasts?
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
Which cytokines do T(fh) release onto B cells to stimulate them?
IL-21
What is the function of FDCs?
Antigen depot
C’ bound antigen binds to CR-½ on FCDs in follicles for recognition by B cells in follicles
In the naïve state, where are T cells found?
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
What is KLRG1?
On which cells is it expressed?
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
At which stages do T cells express IL-7R?
Naïve T cells
Memory T cells
At which stage do T cells express IL-2R?
Effector T cells
At which stage do T cells express IL-15R?
Memory T cells
In summary, what are all the things required for T cell memory formation?
- IL-15, IL-15R
- Derived from IL-7R(high) precursors
- CD4+ T cell signals (IL-2) / DC licensing
Memory T cells expressing E-selectin ligands will be tropic for which organ?
Skin
CLA is an E-selectin ligand
Which memory T cells express CD62L?
Only T(CM) cells
Is repeat exposure required for sustained immunity?
No
Memory cells last for years in the body and provide protective responses even without frequent re-exposure
Which molecules do skin-tropic T(EM) express?
CLA
CCR4
Which molecules do gut-tropic T(EM) express?
α4β7-integrin
CCR9
Which memory T cells express CD62L?
T(cm)
T(em) are located in the periphery, thus do not express it
T(rm) do not express it
What is CD62L?
Aka L-selecting
Allows T cell movement into LNs through HEVs
What are the surface markers of T(EM)?
Which markers are absent?
CCR7-
CCR5+
CD62L-