Immunology 07. Immune Tolerance Flashcards
C is wrong. Should be binding to self-peptide and self-antigen.
Autoimmune diseases are associated with what mutation?
Autoimmune diseases are associated with what mutation?
Mutations in AIRE/FOXp3
Best examples of Tregs? And what is their transcription factor?
Best examples of Tregs? And what is their transcription factor?
CD4+ CD25+ T cells. Transcription factor: Foxp3
Costimulation signal comes from?
Costimulation signal comes from?
1) CD28 on T cells
2) B7 on APC
Define Immune tolerance?
Define Immune tolerance?
Mechanisms that prevent adaptive immune responses to self antigens
Effects of Costimulation? (IMPT!!!)
Effects of Costimulation? (IMPT!!!)
Proliferation and differentiation signal
Upregulation of IL-2 production by T Cells -> T cells proliferation, differentiation
Essentially linking Immune checkpoint and MMR
Essentially linking Immune checkpoint and MMR
Immune checkpoint-> natural process that prevents damage from chronic infection
We propose that we could block the effects of the checkpoint -> so that we can kill of cancer
But immune blockades have its side effects –> reverse peripheral tolerance –> autoimmunity
Notably useful in patients with MMR defects
How can we enhance T cell function with respect to CTLA4?
How can we enhance T cell function with respect to CTLA4?
We can have Anti-CTLA4 antibody
Depletes Tregs and block inhibitory effect of CTLA4 on effector t cell
How do we enhance anti-tumour t cell responses with respect to ctla-4 and pd1?
How do we enhance anti-tumour t cell responses with respect to ctla-4 and pd1?
Antibodies that block these molecules!!
Diminish inhibitory signals for T cells-> Boost anti-tumour T cells responses-> tumour regression
How does Autoimmune regulator (AIRE) work?
How does Autoimmune regulator (AIRE) work?
Allows us to transiently express extra-thymic tissue-specific antigens in the thymus.
Allows for negative selection of TCRs specific for self antigens that are normally not expressed in the thymus
Think about it. How does the thymus select for T cells which wont bind to and recognise self antigens outside of the thymus??? Thymus got the whole body’s repetoire of self antigens meh??? Have. AIRE :)
How does Central Tolerance of T cells work?
How does Central Tolerance of T cells work?
Essentially, after somatic recombination which results in a plethora of different antigen receptors, the body selects for useful receptors and discards useless and dangerous receptors
How does defective Mismatch Repair (MMR) cause high tumour mutational burden? What is it even
How does defective Mismatch Repair (MMR) cause high tumour mutational burden? What is it even
TLDR; DEFECTIVE -> NEOPLASTIC TRANSFORMATION
How does Regulation happen?
How does Regulation happen?
Via Regulatory T cells inhibiting immune response
How does Treg act out its function?
How does Treg act out its function?
Possess **strong TCRs **that recognises SP-SMHC strongly, and act on self-reactive immune cells to suppress their activity
This is the balance that the immune system needs to control the other T cells after danger is gone
In what type of cells do we see Programmed Death-1 (PD-1). What are the effects?
In what type of cells do we see Programmed Death-1 (PD-1). What are the effects?
In chronically activated T cells.
Inhibits activation signalling from TCR complex and CD28
Mutation in foxp3 is associated with?
Mutation in foxp3 is associated with?
Multi-organ autoimmune disease
positive and negative selection follows the principle of which childhood story?
positive and negative selection follows the principle of which childhood story?
Goldilock’s porridge.
Too cold not nice
Too hot will hurt you :)
Revision: 3 signals needed for NAIVE t cell activation?
Revision: 3 signals needed for NAIVE t cell activation?
1) Specific antigen signal (TCR:antigen-MHC complex)
2) Co-stimulation signal (B7:CD28)
3) Cytokines signal (IL2, etc)
Role of PD-1?
Role of PD-1?
1) Limits T cell mediated tissue damage during chronic/persistent infections
2) Inhibits autoreactive T cells
Blocks TCR & CD28 signalling
Similarities and differences between CTLA-4 and CD28? (IMPT)
Similarities and differences between CTLA-4 and CD28? (IMPT)
Similarities:
- Both expressed on T cells
- Both binds to B7
Differences:
- CTLA4 not constitutive, comes up a few days after T cell activation
- CTLA4 binds more strongly to B7 than CD28
- Interaction between CTLA4:B7 delivers negative signal while that between CD28:B7 delivers positive signal
Treg constitutively express which molecule?
Treg constitutively express which molecule?
CTLA-4.
Sequestration of B7 + Downreg B7 expression on APCs
What are some other possible mechanisms of Treg carrying out its function other than via TCR?
What are some other possible mechanisms of Treg carrying out its function other than via TCR?
Cell-cell contact: Constitutive expression of CTLA4 on Tregs blocks and removes B7 from APCs
Soluble factors: Secrete inhibitory cytokines: TGF-B
These are the things that tumour cells try to mimic!!
What are some PRR (pattern recognition receptors) that innate immune system has?
What are some PRR (pattern recognition receptors) that innate immune system has?
1) TLR
2) Lectin
3) NOD-like receptor
4) RIG-like receptor
PRR = Pattern Recognition Receptors
What are the 3 mechanisms of peripheral tolerance? (IMPT!!!)
What are the 3 mechanisms of peripheral tolerance? (IMPT!!!)
1) Ignorance: no signal 1
2) Anergy: signal 1 delivered, but no signal 2 (yes TCR signal but no Costimulatory signal)
3) Regulation: Treg
What are the adverse effects of immune checkpoint blockade?
What are the adverse effects of immune checkpoint blockade?
1) Not antigen specific
2) Leads to reversal of peripheral tolerance of t cells to self antigens-> increased autoimmune damage to organs
Essentially, Immune checkpoint blockade is a proposed therapy for some patients with immunological disease/cancers
Patients with MMR deficiency seems to respond well to immune checkpoint blockade
What are the detriments and benefits of defective MMR?
What are the detriments and benefits of defective MMR?
Detriment: Enhances mutagenesis
Benefit: Enhanced mutagenesis could generate specific tumour neoantigens that can be recognised by adaptive immune system as foreign antigens
What are the two different subsets of immune tolerance?
What are the two different subsets of immune tolerance?
1) Central tolerance: when immature lymphocytes undergo selection process in primary lymphoid organ
2) Peripheral tolerance: mechanisms operating on mature lymphocytes in the periphery
What does negative selection select for?
What does negative selection select for?
Basically selects for T cells with receptors that bind to self-peptide-self MHC complexes with high affinity to DIE by apoptosis
What does positive selection in T cells select against?
What does positive selection in T cells select against?
T cells that do not have any form of binding to any self peptide-self MHC complexes in the thymus
What does Positive selection select for?
What does Positive selection select for?
Lymphocytes which that express TCRs with SOME reactivity for Self-MHC, and thus exhibit MHC restriction
What happens in Ignorance (PT)
What happens in Ignorance (PT)
Interaction between TCR and peptide-self MHC too weak to cause activation of mature T cells in periphery
What happens to T cells when TCR binds to MHC-peptide complex?
What happens to T cells when TCR binds to MHC-peptide complex?
Survival signal
What is anergy (PT)
What is anergy (PT)
Presence of specific antigen signal but not enough co-stimulatory signal.
Anergised cells remain unresponsive even if it subsequently receives signal 2 and signal 3. Makes sense if u look at the examples. if these types of T cells can be activated, means they are auto-reactive!!! Peripheral tolerance’s job is to weed out these type of self-reactive T cells!!!
Examples:
- T cells that binds to immature DCs
- T cells that binds to non-APC normal cells
What is MHC restriction?
What is MHC restriction?
It means that TCRs without some ability to bind to self MHC would not be useful
What is Pathogen associated molecular patterns?
What is Pathogen associated molecular patterns?
Essentially conserved molecular patterns shared by broad classes of pathogens
usually absent in sterile environment
What kind of patients appear to respond well to immune checkpoint blockade?
What kind of patients appear to respond well to immune checkpoint blockade?
MMR deficiency
What triggers DC maturation?
What triggers DC maturation?
Recognition of PAMPs (pathogen-associated molecular patterns)
Which 2 types of contacts do we need to stabilise specific antigen interaction between t cell and APC?
Which 2 types of contacts do we need to stabilise specific antigen interaction between t cell and APC?
TCR-peptide
TCR-MHC
With respect to CTLA4 and PD1, how can cancer evade immunity?
With respect to CTLA4 and PD1, how can cancer evade immunity?
Upreg CTLA4 or PD1 on tumour specific T cells
Expression of PDL1 on tumour cells
Inhibitory effect of Tregs
