lecture 7 Flashcards
What is T cell tolerance?
random TCR (α/β) gene arrangement that leads to T cells expressing TCR that:
a: fail to recognise self-MHC (useless)
b: recognise self-MHC + peptide generated from Ag present in the thymus (potentially dangerous)
c: recognise self-MHC + “any other” peptide not present in thymus (potentially useful)
a die by neglect
b and c are expanded by positive selection
b are eliminated by negative selection
c survive
Why does b survive positive selection but die via negative selection?
b can recognise self-MHC so survives positive selection
binds self-MHC too well so dies via negative selection
Why does c survive over a and b?
it has a population with medium affinity for self-MHC, so should not give an autoimmune response but includes cells that are capable of responding to self-MHC when it contains peptides derived from Ag not present in thymus
What is AIRE?
-AIRE: autoimmune regulator gene; transcription factor involved in central T-cell tolerance
-Highly expressed in thymic medullary epithelial cells
-Allows the expression of many tissue-specific Ag in the thymus - hence negative selection/deletion of T cells that recognise these Ag
-Patients with AIRE deficiency have major autoimmune syndromes
what is B cell tolerance?
random Ig gene rearrangement leads to many B cells potentially expressing self-reactive BCRs
Autoreactive B cells are negatively selected/deleted (in bone marrow)
B cells get a second chance to re-arrange self-reactive BCR or they rearrange another light chain (receptor editing)
What is receptor editing?
new light chain may remove self-reactivity
What can binding of self antigen by immature B cells lead to?
Death/editing or anergy
Leave slightly self-reactive but with low levels of BCR so not considered a risk
What is anergy?
When self-reactive T or B cells become nonreactive without a costimulatory molecule
How can T cells be made anergic?
T cells that are reactive can be silenced
T cells need to see signal 1 and coregulatory molecules before being regulated
Unregulated macrophages do not deliver a co-stimulatory signal to T cells recognising a non-bacterial antigen
What is immunological tolerance?
many Ag are not presented at sufficient levels to activate T cells
Are B cell responses, T cell dependent?
Many cell responses are
If Ag specific T cells are absent/tolerant no help in available -> no antibody response
How do regulatory T cells show tolerance?
CD4+ T cells subset that suppress immune responses crucial for preventing autoimmune responses
Arise in thymus from T cells with high affinity receptors for self Ag
When they become activated they turn other t cells off
What can a deficiency in regulatory T cells lead to?
deficiency of regulatory T cells leads to severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) very serious autoimmune condition
Which cytokines are produced by regulatory T cells and what do they do?
IL-10 and TGF-β inhibit other self-reactive T cells
What are B cells that secrete IL-10 crucial for?
preventing autoimmunity
Why is regulation of immune responses important?
To ensure responses continue only for as long as they are needed
To minimise collateral (tissue) damage
To ensure responses are qualitatively appropriate for the specific pathogen
What are the different CD4+ T cell subtypes and what are their roles?
CD4+ Th1 -> activation of macrophages, NK cells, cytotoxic T cells
CD4+Th2 -> promote responses mediated by eosinophils and mast cells; role in antibody responses, especially IgE
CD4+Th17 -> promote responses against fungi
CD4+Treg/Breg -> suppress unwanted responses
CD4+Tfh -> specialised Th found in GC to help B cells
How do CD4+Th1 cells activate macrophages?
via secretion of cytokines
express CD40L which binds CD40 on macrophage
How do CD4+Th1 cells kill chronically-infected macrophages?
Fas ligand/Fas induce apoptosis
released bacteria destroyed by healthy macrophage -> other cells can then kill the pathogens
What is CD4+Th17 and what is its role?
recently identified subset of CD4+ T cells
secrete IL-17
function to recruit neutrophils early in fungal infections also implicated in autoimmune disease
Are CD4+Treg cells a single population?
single population
What cells make up CD4+Treg?
CD4+CD25+
Some CD8+ T cells have Treg activity
Where do CD4+Treg arise from?
in the thymus nTreg or from circulating T cells in the peripheral tissues (iTreg)
What is the mode of action of CD4+Treg cells?
secretion of suppressive cytokines
TGF-β, IL-10
IL-10 inhibits APC function
How do you know whether CD4+tH1 or CD4+Th2 response?
The type of Th response is influenced by the cytokines that are present when T cells are activated - signal 3
What are the key cytokines involved in naïve T cell activation by APC?
IL-12 and IFN-γ play a key role in induction of Th1 responses
IL-4 important doe induction of Th2 responses
What is the impact of the cytokines present when naïve T cells are activated?
TGF-β, IL-10 - Treg cells
IL-21, ICOS - follicular helper T cells
IL-6, IL-17 - Th17 cells
IL-2, IFN-γ - Th1 cells
IL-4, IL-5 - Th2 cells
What does polarisation of CD4+ T cell responses cause?
Th1 cytokines - promotes commitment to Th1, inhibit development of Th2,Th17
Th2 cytokines - promote commitment to Th2, inhibit development of Th1, Th17
Th17 cytokines - promote commitment to Th17 cytokines, inhibit development of Treg
Treg cytokines - inhibit Th1,Th2,Th17 responses
How do Treg cells allow a successful pregnancy?
Stops rejection of baby which has antigens from father as the tregs turn off the rejection
What is the importance of polarised responses?
ensures correct responses for different types of pathogens
can go wrong may lead to allergy (excessive Th2)
control of autoreactivity/pregnancy
