- B cells - TCRalpha/beta + T cells (CD4/8+)

- pentameric Ab - low affinity - poor/no memory

- Ab factories - can be short or long lived - locate to mucosa (long-lived) /bone marrow (short-lived)

- what type of antibody to make - e.g. high affinity IgG - change the receptor and test it for higher affinity; somatic hypermutation - part of the lineage that has been generated inside the pool

- site of CD4 T cells and B cell interaction - Class switching - Affinity maturation

- Short/long lived - Average half-life: 6-9 mo’s - Migrate through tissues

- Recognise MHCII-peptide complexes - Many effector cell subsets

- Recognise MHCI-peptide complexes - Various differentiation states; mostly Tc1

Immune memory Flashcards by Grace Beglan

A natural experiment in immune memory

Measles in the Faroe Islands
1781: outbreak
1782-1845: measles free
1846: 2nd outbreak (>70% incidence)
“of all the aged people still living on the Faroes who had measles in 1781, not one was attacked a second time”
“all the old people who had not gone through measles in 1781 were
attacked by disease in 1846”
long-term immune memory, without continuous exposure

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Memory cells:

B cells
TCRalpha/beta + T cells (CD4/8+)

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Population level factors of immune cellular memory

changed frequency of specific clonally expressed receptors
lymphocytes (rapid proliferation and persistence)

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Cellular level factors of immunological memory:

altered gene expression profiles
altered migration
altered activation requirements

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How does migration alter at the cellular level of immunological memory?

changed surface receptors

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How are activation requirements altered in the cellular level of immunological memory?

changed surface receptors
and biochemistry

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T-cell independent B cell activation and memory

bind repetitive, mutlimeric antigen epitopes
cross-linking B cell receptors; sufficient stimulus
some clonal expansion
specific antibody production (e.g. IgM); doesn’t get stronger

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T-cell dependent B cell activation and memory

B cell recognises monomeric epitope
Clonal expansion
Ab production
Instructional developmental pathways

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B cell activation and memory

can be Tc-(in)dependent
different waves/consequences

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IgM

pentameric Ab
low affinity
poor/no memory

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plasma cells

Ab factories
can be short or long lived
locate to mucosa (long-lived) /bone marrow (short-lived)

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Instructional development pathways of T-cell dependent B activation and memory

some become plasma cells
some form a memory pool
class switching

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class switching

what type of antibody to make
e.g. high affinity IgG
change the receptor and test it for higher affinity; somatic hypermutation
part of the lineage that has been generated inside the pool

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Germinal Centre

site of CD4 T cells and B cell interaction
Class switching
Affinity maturation

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B cell commitment to Ig
production versus memory

occurs early after activation

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Memory B cells

Short/long lived
Average half-life: 6-9 mo’s
Migrate through tissues

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Describe B cell activation in detail

initial burst gives rise to the germinal centre
fast division
occurs early but continuously through passage of time

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B cell memory: CD4+ dependency

Help within the germinal centre
mechanism to retain specificity (and prevent autoimmunity) in the face of a changing BCR

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Repeated B cell epitope exposure leads to increased:

Ig amounts (esp. class-switched)
increased affinity

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TCRab+ T cell activation (summary)

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Naïve CD4 or CD8+ T cells

initially stimulated by DCs
most stimulated in the lymph node

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Naïve CD4 or CD8+ T cells DC stimulation

High MHC levels
Co-stimulation (CD80, CD86 via CD28 on T cell)
Produce cytokines, to direct development

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CD4+ T cells

Recognise MHCII-peptide complexes
Many effector cell subsets

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CD8+ T cells

Recognise MHCI-peptide complexes
Various differentiation states; mostly Tc1

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Types of CD4+ T cells

- TH1 - TH2 - TH3 - TH9 - TH17 - TFH - nTREG - iTREG

Tc1

activity via cytoxic mediators and IFNgamma

A complex set of molecular interactions control T cell activation at the “immunological synapse”

1. TCR recognises MHC 2. CD8 stabilises low-affinity interaction 3. other adhesive molecules cement organisation

Why does CD8+ need to stabilise the low affinity interaction?

- needs to engage with enough TCRs to build up signal - co-stimulation - bind CD28: positive signal - Go-magnitude

Brake on the CD4/8+ activation

- CTLA-4 up regulation - transcriptional activation goes down - dominance oscillation

immunological synapse

- tight space between the T cell and the APC - junction important for function of T cells - Tc1 produce perforin and granzymes to lyse the target cells - pour it into the synapse: high local concentrations; minimise bystander damage

Size-dependent spatial organisation/segregation in the immunological synapse

- TCR is v. small; how does it reach MHC? - strong and sticky adhesion molecules in the outer ring stabilise the synapse - TCR is in the inner compartment - cSMAC

cSMAC

- stimulatory complex

The synapse focuses:

- Secretion - Cytotoxic activity - Cytokine delivery - Membrane trafficking

Naive T cells

- Each TCR at very low frequency - Migrate through lymph nodes

Activated T cells

- high frequency - perform a diverse set of functions - migrate to the site of infection, attracted by local inflammation - instructed to return to DC origin tissue where the DC originated fro

Memory T cells

- Intermediate frequency - Easier to activate - Re-circulate through peripheral tissues (+ lymph nodes)

LCMV CD4+ (mice)

Naive: < 1 in 106 Active: 1 in 40 Memory: 1 in 2000

EBV CD4+

Naive: < 1 in 106 Active: 1 in 30 Memory: 1 in 103-104

LCMV CD8+

Naive: < 1 in 106 Active: 1 in 2 Memory: 1 in 100

EBV CD8+

Naive: < 1 in 106 Active: 7 in 10 Memory: 1 in 100-1000

cell surface molecules relate to

- adhesion - migration of cell types

CCR7

- chemokine receptor guiding cells to lymph nodes - High in naïve T cells - Lost in activated T cells - Partially regained in some memory cells

CD62L

- integrin - binding the addresin that sits on lymph nodes - High in naïve T cells - Lost in activated T cells - Partially regained in some memory cells

CCRR7 and CD62L in activated T cells:

- Downregulated - allows lymphoid exit - migration to inflamed peripheral sites

CCRR7 and CD62L in memory T cells

central: re-express effector: no re-expression

CD44 helps cells:

1) Stick to endothelium 2) Interact with other cells 3) Migrate through tissues

CD44 expression profile

- low on naïve - very high on activated; allows more interactions - intermediate on memory

LFA-1

- integrin - Increases with Tc activation - mediates cell–cell interaction

LFA-1 cell:cell interactions

- Tc:APC - Tc:target cell

IFN-γ / IL-4 / perforin

- effector molecules - Absent in naïve cells - Very high in activated cells - Lower but rapidly inducible in memory cells

Tc turnover rate experiments

- BrDU labelling in vitro/vivo (nt analogue; division marker) - 2H glucose in human volunteers - pools continue to divide - measured with division markers - naive cells accumulate over time - memory cells accumulate faster

All T cells divide…

just at different rates

BrDU

- nucleotide analogue

naive T cell turnover rates

- slow - 116-365cDs

memory T cell turnover rates

- fast - 15-70cDs - finite - affected by envrt; "non-specific" signals

activated T cell turnover rates

- FAST - 10-12hrs

T cell pools

- constrained

Explain the constraint of T cell pools

- rate of cell death must match entry + division

What are the consequences of the constraint of T cell pools

- competition! - selective memory - limited space - growth/survival signals

naive T cell pool

- fixed - affected by thymic export, cycling, and death

activated T cell pool

- temporarily flexible - affected by cell death

memory T cell pool

- fixed - affected by death

Non-specific signals affecting memory cell turnover - memory CD4+/CD8+ adoptive transfer expt.s

- survive in naïve recipients; no requirement for activating antigen (needs IL7) - survive in MHC-deficient recipients; no requirement for self-MHC antigen - in these contexts, naive T cells would die - inflammatory mediators (IFNs, IL15) drive proliferation

Many patterns observed at the level of recognition and repetoire

- within a specific peptide response - some retained, some expanded, some lost - a mixture of clonal persistence, exhaustion and competition

Why is specificity and repetoire so important?

- not all responses are protective - broad specificity decreases the risk of immune escape - focus response on most effective

effector memory

- do not express CCR7, CD62L integrin - instead, express other CCR and homing molecules (chemokine Rs) to migrate through tissues and spleen - rapid transition -> function

tissue memory

subset of effector memory cells specialised to reside in a particular tissue

central memory

- CCR7, CD62L+ - preferentially migrate through lymph nodes - long-lived - more cDs prior to differentiation; slower (still large effect)

CD4+ characteristics and interactions

- diverse repetoire - gradual decline across time

CD8+

- v. large clone sizes - stable across time

Modelling memory

1) linear differentiation model 2) bifurcative differentiation model 3) self-renewing effector model (not interactive) - probably all of these processes occur; they are not exclusive

recall responses - the basics

often have a mixture of non- and pre-committed cells

recall response - an example

- primary response: naive -> activated Th0 -> polarised - secondary response: mixed recall environment (with dominant dynamics)

Th1

IL12, 18

Th2

IL4

Give the possible explanation for mixed recall environments - the basics

1. non-committed memory cells 2. variation in commitment level

Give the possible explanation for mixed recall environments - the potentials

- increasing commitment w/ cell divisions - pre-committed/partially committed/ totally committed

Give the possible explanation for mixed recall environments - the prediction

memory pool w/ mixed commitment enables biased but flexible secondary response

T cell exhaustion

- exhausted phenotype: overstimulated by persistent viral infections - resource depletion - division cessation - genome repair - immunological memory hesitates - AIDS

What is immune memory?

- an adaptive immune phenomenon - faster responses to previously experienced circumstances - changes is repertoire - changes is cellular state - different activation requirements - different homing - intrinsic and extrinsic signals

Why do we need to know about immune memory?

- vertebrate strategy for survival in a dirty world - how vaccines work; make vaccines work better (and for longer)

Immune memory Flashcards

(82 cards)