L7: T Cell Activation Flashcards
What is immunological tolerance needed for?
- random generation of a range of BCR& TCR
- self reactive specifcities to be produced
- without it autoreactivity would lead to a serious pathology
TCR gene rearrangement leads to T cells expressing TCR that what?
- fails to recognise self MHC
- recognises self MHC and peptide generated from Ag present in the thymus (potentially dangerous)
- recognises self MHC and any other peptide present in thymus (potentially useful)
What will happen to T cells expressing TCR that fails to recognise self MHC?
It will die by neglect as there will be no +ve selection survival signal
What will happen to T cells expressing TCR recognises self MHC?
Cell are expanded by +ve selection. Then if:
- recognises peptides in thymus, eliminated by -ve selection
- recgonises peptides not present in thymus, survives
What population T cell is desired to survive selection and why?
Those recognising self MHC and antigens not present in Ag because
- will have medium affinity for self MHC so shouldn’t give autoimmune response
- cells also capable of responding to self MHC when it contains peptides found in pathogens
Give an example of a self Ag not expressed in the thymus
Insulin
What is the role of AIRE (autoimmune regulatory protein)?
Its a txn factor with a key role in tolerance induction
- allows expression of normally tissue specific Ag in thymus and thus deletion of T cells that recgonise these Ag
What can deficiency of AIRE result in?
Major autoimmune syndrome
Random Ig gene rearrangment can lead to what 2 main outcomes?
- B cells expressing self reactive BCR
- B cells expresing BCR that recognise Ag present in bone marrow
What can happen to immature B/T cells that bind self Ag and why?
They may undergo further light chain gene or TCR alpha locus rearrangements, in the possibility of expressing a BCR/ TCR that is no longer self reactive respectively
Name 3 methods by which tolerance can be acquired/ developed?
- gene rearrangement
- clonal anergy
- immunological ignorance
- privelleged sites
How can tolerance be acquired through clonal anergy?
Lymphocytes that recognise self Ag can become unresponsive (anergic)
- T cells that encounter Ag in the absence of co stimulation become anergic
- anergy can lead toperipheral tolerance of T cells
How can immunological ignorance cause tolerance?
Many Ag aren’t presented at sufficient levels to activate T cells
How can privelleged sites lead to tolerance?
These are sites of body that are able to tolerate introduction of Ag without eliciting an inflammatory immune response, so Ag is sequestered from immune system
- BB barrier stops lymphocytes going into CNS where it might recognise self Ag
What will happen if Ag-specific T cells are absent/tolerant?
There will be no Ab response as many B cell responses are T cell dependent
What are regulatory T (Treg) cells and what is their role?
They are a CD4 subset that regulate other T cells by supressing immune response
- crucial for preventing autoimmune diseases
How are Treg cells formed?
- they arise in thymus from T cells with high affinity receptors for self Ag (n (natural) Treg) or
- can be induced in periphery (iTreg)
Why do immune responses need to be regulated?
- to ensure responses continue only for as long as they are needed
- to minimise collateral tissue damage
- to ensure responses are qualitatively appropiate
How do CD4 Th1 cells activate macrophages?
- Via secretion of cytokines e.g. IFN-gamma, TNF-alpha
- Or via CD40L binding to CD40
Name the effector T cells naive CD4 T cells can differentiate inro following successful activatoin
CD4 Th1/2/17, CD4 T reg or CD4 Fh
What is the role of CD4 Th1
Activates macrophages, NK cells and CTLs
What is the role of CD4 Th2?
- Promotes responses meidated by eosinophils and mast cells.
- Also plays role in Ab responses, especially IgE
What is the role of CD4 Th17?
Promotes responses against fungi
What is the role of CD4 Treg?
Suppresses unwanted immune response
What is the role of CD4 Tfh
Specialised Th found in GCs to help B cells
- can produce Th1/2 and Th17 cytokines)
How does CD4 Th1 kill chronically infected macrophages?
- Fas ligand/ Fas induced apoptosis
- released bacteria desroyed by healthy macrophages
- other cells can then kill the pathogens
What 2 CD4 T cell subsets can secrete cytokines?
Th17 and Treg
Explain CD4 Th17 cytokine secretion
- secretes IL-17
- functions to recruit neutrophils early in (fungal) infectinos
- also implicated in autoimmune diseases
Explain CD4 Treg cytokine secretion
- uses a mix of cells e.g. CD4+, CD25, CD8+, double -ve cells)
- supresses T cell response
How do CD4 T cell subsets secrete cytokines
Via the scretion of suppressive cytokines (TGF-beta and IL-10_ and can also involve cell/cell contact
- IL-10 inhibits APC function
What is the type of Th response influenced by?
Cytokines present when T cells are activated
Explain the roles of common cytokines
- IL 12 and IFN-gamma play a key role in induction of Th1 response
- IL 4 is important for induction of Th2 responses
Name what each CD4+ cytokine promtes (their polarised responses)
- Th1 promotes Th1 and inhbitis Th2&17
- Th2 promotes Th2 and inhbits 1&17
- Th17 promtes T17 and inhibts Treg
- T reg inhibits of Th1,2&3 and allows succesful pregnanacy
Why are polarised responses important?
- ensures correct response for different types of pathogens
- control of autoreactivity/ o
pregancy - if it goes wrong may lead to allergy via excessive Th2
