L7 - Regulation of the immune response Flashcards
Why do we need immunological tolerance?
Random generation of repertoire of BCR & TCR
Self-reactive specificities will be produced
If no tolerance, could be a serious problem – self-destruction
How do lymphocytes become tolerant?
If:
- They encounter Ag in central lymphoid organs (BM/thymus) when they are immature: central tolerance
- They encounter Ag in the peripheral tissues in the absence of other necessary signals: peripheral tolerance
Tolerance through clonal deletion
Engagement of receptors on immature B or T cells leads to their deletion
Occurs in thymus & bone marrow
Death occurs by apoptosis
Only works for Ag to which developing lymphocytes are exposed
Random TCR gene rearrangement leads to T cells expressing TCR that…
a) Fail to recognise self-MHC
b) Recognise self-MHC + peptide generated from ‘self’ Ag present in the thymus
c) Recognise self-MHC + ‘any other’ peptide
a die by neglect – no positive selection survival signals
b & c expanded by positive selection
b then eliminated by negative selection – binds self MHC too well
c are they only ones that survive – have medium affinity for self-MHC
Why are TCRs that have a medium affinity for self-MHC the only ones that survive?
Shouldn’t give an autoimmune response, but includes cells that are capable of responding to self MHC when it contains peptides derived from pathogens
Not all self-Ag are expressed in the thymus
Why?
eg. insulin
Insulin is very tissue specific (beta cells in the pancreas) so you would never predict it to be expressed in the thymus as it doesn’t work there
What is AIRE?
Autoimmune regulator protein
Transcription factor
Key role in tolerance induction
What does AIRE do?
Allows the expression of normally tissue-specific Ag in the thymus & hence deletion of T cells that recognise these Ag
What happens if you get a deficiency or mutation in AIRE?
Causes major autoimmune syndrome
Causes autoimmune T cells
BCR generation/bone marrow selection & tolerance
Random Ig gene rearrangement leads to B cells expressing self-reactive BCR
Similar to T cells, autoreactive B cells are negatively selected in bone marrow
Unlike T cells, B cells get a second chance to re-arrange any self-reactive BCR – receptor editing
What is receptor editing?
Immature B cells that bind self-antigens may undergo further light chain gene rearrangements – possibility of expressing a receptor that is not self-reactive
Similarly immature T cells that fail positive selection can also undergo further rearrangements of the TCR-alpha locus to produce a different receptor
Tolerance through clonal anergy
Lymphocytes that recognise self Ag are rendered unresponsive – anergic
Immature B cells: when receptors encounter Ag that is NOT multivalent – downregulate BCR
Anergy is important in peripheral tolerance: T cells that encounter Ag in the absence of co-stimulation become anergic – signal 1 without signal 2
What does anergy mean?
Anergy is defined as the lack of responsiveness to an antigen despite the presence of antigen-specific lymphocytes
Other mechanisms of tolerance
Immunological ignorance
Privileged sites
Many B cell responses are T cell dependent
Regulatory T cells
Regulatory B cells
Other mechanisms of tolerance:
Immunological ignorance
Many Ag are not presented at sufficient levels to activate (or tolerise) T cells
Needs to be a threshold of antigen
Other mechanisms of tolerance:
Privileged sites
Ag sequestered from immune system (suppressive cytokines also prevalent)
Eg. eye, testis, CNS (barriers in place)
If you damage your eye & immune system cells get in – you may get autoimmunity in your eye as you’ve broken the barrier
Other mechanisms of tolerance:
Many B cell responses are T cell dependent
If Ag-specific T cells are absent/tolerant no help is available no antibody response
Other mechanisms of tolerance:
Regulatory T cells
CD4+ T cell subset that suppress immune responses – turn off IR
Crucial for tolerance & suppressing autoimmune responses
Arise in thymus from T cells with high affinity receptors for self-antigen n(atural)Treg – can also be induced in the periphery (iTreg)
nT-regs & iT-regs
nTreg controls the cells that escape negative selection that aren’t Treg
If an autoreactive cell in the periphery is causing an issue, it can be induced into an iTreg to escape natural selection
Multiple layers of control
What happens if you get a deficiency in Treg?
Leads to a severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome)
Other mechanisms of tolerance:
Regulatory B cells
Specific B cells to dampen down the immune response
B cells recently described that secrete IL-10 are crucial in preventing autoimmunity
Why do we need to regulate immune responses?
To ensure responses continue only for as long as they are needed
To minimise collateral (tissue) damage
To ensure responses are qualitatively appropriate – ie. Right for the specific pathogen
What happens once naive CD4 T cells are activated?
naïve CD4 T cells differentiate into effector T cells – do not require co-stimulation anymore
What are effector T cells?
TH-1 TH-2 TH-17 T(reg) T-FH
What are CD4+ cells?
T helper cells
What are CD8+ cells?
Cytotoxic T cells
What do CD4 TH-1 cells do?
Activation of macrophages, NK cells, cytotoxic T cells
What do CD4 TH-2 cells do?
Promote responses mediated by eosinophils & mast cells
Role in antibody responses, especially IgE
What do CD4 TH-17 cells do?
Promote responses against fungi
What do CD4 T(reg) cells do?
Suppress unwanted responses
What do CD4 T-FH cells do?
Specialised TH found in GC to help B cells
Can produce TH1, TH2 & TH17 cytokines
How do CD4 TH-1 cells activate macrophages?
Via secretion of cytokines: eg. IFN-gamma, GMCSF, TNF-alpha
CD40L binding to macrophage CD40
How do CD4 TH-1 cells increase the efficiency of macrophages?
Macrophages eats & destroy pathogens
Puts a peptide on its class II MHC on the surface which is recognised by TH1 cells – makes the macrophage eat things a lot more effectively
How do CD4 TH-1 cells increase microbicidal activity of macrophages?
Increased fusion of phagosomes with lysosomes
Increased synthesis of oxygen radicals, NO, proteases
How do CD4 TH-1 cells kill chronically infected macrophages?
Fas ligand/ Fas induce apoptosis
Released bacteria destroyed by healthy macrophage
Other cells can then kill the pathogens
How do CD4 TH-17 cells act against fungi?
Secrete IL-17
Function to recruit neutrophils early in (fungal) infections
Implicated in autoimmune disease
Suggested to be the evolutionarily ‘oldest’ form of acquired immunity
Why are CD4 T-reg cells different from the other types of T cells?
Not a single population
Mixed bag of cells – CD4+, CD25+, CD8+
Double negative
Arise in the thymus (nTreg) or from circulating T cells in the peripheral tissues (iTreg)
What is the type of TH response influenced by?
The cytokines that are present when T cells are activated (signal 3)
What is signal 3?
The cytokines that are present when T cells are activated
What are the key cytokines involved in signal 3?
IL-12 & IFN-gamma play a key role in induction of TH1 responses
IL-4 important for induction of TH2 responses
Cytokines present when a naïve T cell is activated determine the effector T cell it becomes as a consequence of key transcription factor activity
What do TH-1 cytokines do?
Promote commitment to TH1
Inhibit development of TH2 & TH17
What do TH-2 cytokines do?
Promote commitment to TH2
Inhibit development of TH1 & TH17
What do TH-17 cytokines do?
Promote commitment to TH17 cytokines
Inhibit development of Treg
What do T-reg cytokines do?
Inhibit TH1, TH2 & TH17 responses
What is the importance of polarised responses?
Ensures correct responses for different types of pathogens
Infection – one route may be better for the host
Allergy – excessive TH2
Autoimmune disease
