T cell development and self tolerance Flashcards
Define immunological tolerance
The mechanism by which lack of immunological reactivity is induced and maintained (e.g. against self antigens, commensal microbiota)
- it is antigen specific
What is immunoscenesce and how does thymic involution contribute towards it?
Preogressive deterioration of immune responses mainly associated with age
Thymus is fully developed by birth but increases in size during puberty and atrophies with age (thymocytes become fat)
- The reduced production of T cells doesn’t completely impair immunity as the T cell repertoire is long lived but it contributes
What determines the TCR repertoire?
TCR genes undergo DNA rearrangements in thymus
- generation of the TCR repertoire involved random mechanisms and the specificity of TCR in the immature repertoire is also random and will include cells with receptors that are harmful, useless, and useful.
How does sorting of the cells within the TCR repertoire occur
Via selection dependent on if thymocytes express restricted TCR
How do naive T cells differ from mature t cells?
They are self-MHC restricted and self tolerant
Only cells that present antigen receptor with appropriate affinity for the peptide presented in self MHC complexes complete their maturation and form the peripheral T cell pool
Where and how do T cell cells mature ?
Where and how do they die?
T cells mature in thymic stroma (epithelial cells and connective tissue)
- thymocytes are intimately linked during development to ep. cells
- the stroma provides the microenvironment for t cell development and selection
T cells also die in thymus
- without inducing inflammation or any change in thymic size.
- thymic macrophages phagocytose apoptotic thymocytes
What happens to thymocytes that can recognise self MHC expressed on cortical epithelial cells?
SURVIVE
- via induction to survive, differentiate and mature
What happens to thymocytes that cannot recognise self MHC expressed on cortical epithelial cells?
DIE
- via apoptosis
Define positive selection
Retention of thymocytes expressing TCR that are restricted in their recognition of self MHC
- if the TCR cannot recognise self MHC it undergoes apoptosis –> useful selection
Define negative selection
How does it work?
Removal of thymocytes expressing TCR that recognise self antigens presented by self MHC –> harmful selection
- Dendritic cells and macrophages at cortico-medullary junction are APC expressing MHC1 and 2 and present self peptides to T cells
- modest binding of double positive T cell–> survival
- strong binding –> apoptosis
Positive selection is the mechanism for….
Negative selection is the mechanism for….
Where do they occur
MHC restriction
Tolerance induction
They occur in distinct microenvironments after interaction with different stromal cells (ep. cells/dendritic cells)
How does the thymus express tissue specific antigens?
What happens in disregulation of this mechanism?
- transcription factor (AIRE) expressed at high levels by thymic medullary epithelial cells
- mutations in AIRE –> AI polyendrocinopathy with candidiasis and ectodermal dysplasia (APECED)
How is self tolerance established to antigens that cannot be expressed in the thymus?
e.g.
Why is this important?
e.g. antigens expressed during puberty, insulin, lactose
PERIPHERAL TOLERANCE: tolerance to foreign antigens is induced and maintained in mature thymocytes
- important as you dont want an immune response against harmless antigens (food), allergy and you dont want excessive lymphocyte activation during normal protective responses against infections
How is peripheral tolerance facilitated?
- Ignorance: lymphocytes fail to recognise or respond to self
- Clonal anergy: binding of Ag makes lymphocyte unresponsive
- Clonal expansion: continues stimulation by persistent antigen may ‘wear out’ responsive cells
- Suppression: interaction with other cells (and cytokines) may inhibit responsiveness
Peripheral tolerance can occur via IGNORANCE
Explain this
How can this go wrong?
Anitgens automatically sequestered from immune system
- if they are released, AI can develop (vasectomised males have anti-sperm antibodies)
- good location for tissue grafts
T cell cannot react with cells bearing the Ag
Known as immunologically privileged sites
Physical trauma in an eye can initiate AI –> blindness in both eyes = SYMPATHETIC OPHTHALMIA
Peripheral tolerance can occur via CLONAL ANERGY
Explain this
How is this used therapeutically?
- Presentation without co-stimulation
- CTLA4 signalling
Blocking CTLA4 promotes tumour rejection as CTLA4 limits immune response to tumours.
- Anti- CTLA4 antibody is approved for tumour immunotherapy
Peripheral tolerance can occur via CLONAL EXPANSION
Explain this
What is clonal exhaustion?
- Activation induced cell death: repeated stimulation of T cells by persistent antigens –> apoptosis of activated cell
This can lead to acute infection: clearance of virus
and chronic infection: persistence of virus
Clonal exhaustion: elimination of t cells specific for abundant peripheral antigens
Peripheral tolerance can occur via SUPPRESSION
Explain this
What happens if this goes wrong?
Therapeutic potential?
Treg cells suppress activation of effector responses and are critical for regulatory homeostasis and tolerance to self
Deficiency of Treg is associated with aggressive AI/IPEX
- strengthen/reestablish self tolerance in AI
- induce tolerance to non-self antigens in allergy, transplant
- induce tumour immunity in cancer patients
An antigen can be tolerogenic and immunogenic
What are determinants?
- How/where/when it is encountered
- concentration
- persistence
- tissue distribution
What antigen properties generally induce tolerance?
- Small, soluble, non-aggregated antigens
- Encountered in very small or very large dose
What antigen properties generally induce immune response?
- Large, aggregated, complex antigens
- Encountered in intermediate dose
The route of administeration of an antigen can influence whether is it immunogenic or tolerogenic
Give examples of this
- Intratracheal and orbital exposure stimulate Tregs
- Tolerance by interaction of food proteins with GALT in intestinal transit
What is hyposensitisation immunotherapy oral immunotherapy (OIT)
- using small amount of allergens to induce antigen specific tolerance
- continuous administeration of allergen promotes development and maintenance of tolerance
- oral/sublingual desensitisation immunotherapy for peanut allergy
