Immune Regulation Flashcards
what is the central mode of regulation?
repertoire selection
What is the peripheral mode of regulation?
peripheral deletion
anergy
regulatory receptors
regulatory T cells
When does central tolerance take place?
during formation of T and B cells to remove auto reactive T and B cells
How does deletion of T cells in periphery occur?
apoptosis of T cells
targets mitochondrial pathway of killing
extrinsic or intrinsic
How does intrinsic deletion through apoptosis occur?
lack of IL-2 and IL-7 leads to upregulation of p53 - proapoptotic factors
How does extrinsic deletion through apoptosis occur?
through Fas/FasL pathway
What causes suppression of T cell responses/inhibition
response to chronic stress
tumours, viral infection
How does inhibition via CTLA-4 occur?
cytotoxic T lymphocyte associated protein 4 (CD152) binds CD80 and CD86 on APCs. inhibits via decoy or intracellular activity
How does inhibition via PD-1 occur?
programmed cell death 1
binding to PD-L1 and PD-L2
important in modulating immune responses
What is exhaustion?
persistent stimulation of T cells
What is stalemate?
virus/tumour-immune equilibrium
What are 4 medications used to manipulate checkpoint blockades?
- ipilimumab
- involumab
- pembrolizumab
- atezolizumab
What is the proposed role of PD1
suggested it can establish and reverse HIV latency
Where does generation of Treg cells occur?
can occur in thymus or periphery
What is the dual role of TGFb
TGFb is typically anti-inflammatory but can also stimulate naive T cells
What are 2 effector functions of Treg cells
can act on other T cells or APCs
important balance in immune responses
What are the suppressive cytokines of Treg cells
TGFb and IL-10
leads to alteration of transcription program
How do Treg cells promote cell death?
express granzymes and perforin usually in CD8 T cells
requires Tregs to have long stimulation
How do Treg cells disrupt function?
reduce metabolic capacity, which means less energy for effector functions
high affinity IL-2 receptor
displaced T cell interactions w DC
Describe the role of granzyme B in inflammation and apoptosis
granzyme B triggers apoptosis but can also have other inflam effects
What is tolerance?
process by which immune cells are made non-responsive to self-antigens
What is AIRE?
an important regulator for -ve selection in thymus
eg. in presence of AIRE protein, thymic medullary cells express tissue-specific proteins leading to deletion of tissue-reactive T cells
eg. in absence of AIRE, T cells reactive to tissue-specific antigens mature and leave the thymus
What is APS Type 1
lack of AIRE resulting in autoimmune reactions against endocrine glands
What is peripheral tolerance for B cells?
second checkpoint, similar to central tolerance
receptor editing doesn’t happen bc these cells are mature and can’t rearrange light-chain loci
Link between somatic hypermutation and auto reactive B cells?
auto reactive B cells can form during somatic hypermutation
will be at a competitive disadvantage in GC reactions
How does antigen sequestration/ignorance occur?
happens in situations where escaped cells don’t ever see antigen
can happen in sympathetic ophthalmia
How does suppressing immune response lead to anergy?
inhibition of TCR signalling through Cbl-b which attaches to ZAP-70
ubiquitinatino of complex leads to degradation
When does molecular mimicry occur?
when antigen is structurally similar to self-proteins
How do auto reactive cells become anergic?
when stimulated with antigen under non-inflam conditions and made active again with sufficient stimulation
What 2 situations break down tolerance mechanisms?
- molecular mimicry
- alloreactivity
What are tolerogenic DCs?
DCs which still present Ag but down regulates co-stimulatory molecules and up regulates inhibitory molecules
Use an examples to describe how gut microbiota can affect DCs
polysaccharide A of B.fragilis interacts with TLR2 of DCs to alter signalling and protects against experimental colitis
cause disease and metabolic conditions
What does central tolerance involve for T cells?
removing auto reactive T lymphocytes during development
How does peripheral tolerance work in T cells?
occurs via self antigen presentation or antigen sequestration
What are 3 ways that Tregs can become activated against auto antigen?
- produce cytokines to dampen immune response
- direct killing of auto reactive cells
- disrupting function of auto reactive cells so its harder to exert effector functions
