Lecture 17; Central and Peripheral Tolerance Flashcards
What is immunological tolerance?
Immunologic tolerance is defined as ‘unresponsiveness to an antigen that is induced by a previous exposure to that antigen’
How can lymphocytes display tolerance?
When a specific lymphocyte (B or T) encounters an antigen it maybe activated (response) OR inactivated/eliminated (tolerance)
Where is tolerance learnt?
Ø The immune system has to be “educated” not to recognise self - in this way tolerance is “learned”
Ø Immune system ”education” takes places in lymphoid tissue (primary and secondary tissue)
Ø A failure of self tolerance results in autoimmunity
What is peripheral tolerance?
Once cells leave primary lymphoid tissue and start circulating through secondary lymphoid tissue they can undergo peripheral tolerance.
Backup – silences any lymphocytes that recognize self but escaped central tolerance
What are the possible mechanisms of peripheral tolerance?
- Peripheral Tolerance
Some self-reactive lymphocytes enter peripheral tissues. They maybe inactivated (i), deleted (ii) or suppressed (iii) by the regulatory T cells. Another mechanism is clonal ignorance (iv).
Describe the classification of T cells undergoing positive selection in the thymus?
Non-selection of cells that
- fail to bind self MHC
Positive selection for cells that are:
MHC restricted*
Weakly self-reactive
- Clonal deletion
- Receptor Editing
- Anergy
- Become Tregs
Strongly self reactive; - Negative selection of strongly self-reactive cells (removed) OR made self-tolerant
What happens if you delete Tregs?
Autoimmunity
How do we gain tolerance against tissue specific antigens that are not normally expressed in the thymus?
AIRE – Autoimmune regulator
Interacts with transcription proteins which enables some tissue specific proteins to be expressed in the thymus
AIRE absolutely critical as not every self protein is present in the thymus
What do patients with defective AIRE have?
APECED – Autoimmune polyendocrinopathy candidasis ectodermal dystrophy
Autoimmune disease
What happens in B cell tolerance?
No reaction -> B cells are good, go to periphery and act as mature B cells
(Strong) 1. Immature B-cells recognise self
antigens (multi- valent)
a.Edit BCR sequence
b.OR clonal deletion
(Weak) 2. Self antigen
recognition is weak (low valent), B cells become unresponsive (anergic)
Describe B cell receptor editing?
Some B cells that self react in during central tolerance testing can undergo receptor editing
- B-cell expresses receptor that is strongly cross-linked
- Surface expression of IgM is decreased and RAG expression is maintained
- Enables production and expression of a new light chain
- If the new receptor is not self reactive then the cell is ‘rescued’
What are the problems with diversity?
- B cell receptors can hyper-mutate somatically.
- MHC in peripheral tissue is loaded with self peptides.
- Enormous potential for cross-reactivity to self.
- The bone marrow and thymus remove only the most reactive cells.
Is the self reaction problem really that bad?
A relatively small number of antigens can serve as auto-antigens:
◦ Each APC expresses ~105 MHC molecules
◦ Potential of ~10,000,000 self peptides/APC
◦ It takes ~10 identical peptides per APC to fully activate a T cell
◦ Therefore only a very few peptides will be present at high enough level to present a potential auto-antigen
◦ Because these are likely to be common housekeeping proteins, they will be present in the thymus
Message; Context influences communication
What are the four main mechanisms of peripheral tolerance?
1) Clonal Deletion
2) Clonal Anergy
3) Ignorance (Barriers)
4) Regulation
What can causes clonal deletion in peripheral tolerance?
- T-lymphocytes that recognize self antigens without inflammation
- OR are repeatedly stimulated by antigens are triggered to die by apoptosis
What is the mechanism for peripheral tolerance clonal deletion?
- Major mechanism for CD4+ cells is via activation of the death receptor
- Death receptor=FAS(TNFreceptor family)
- Ligand is FasL(homologouswithTNF)
Describe how peripheral tolerance leads to clonal deletion when t cells are repeatedly stimulated?
Repeated antigen stimulation without inflammation leads to Fas expression on T-cell = apoptosis
What is clonal anergy also known as?
(functional unresponsiveness)
When happens clonal anergy (peripheral tolerance)?
Antigen presented inappropriately
• Absence of second co-stimulatory signal.
• Or may involve the presence of of an inhibitory receptor e.g CTLA4
Prolonged antigen exposure without co-stimulation = signal block and anergy
Give an example of clonal anergy type one;
- Full activation needs MHC-TCR AND B7-CD28
* Without co-stimulation there is a signaling block
Give an example of clonal anergy type 2;
- Full activation needs MHC-TCR AND B7-CD28
- Co-stimulation but also expression of the inhibitory receptor CTLA-4
No external stimulation so CTLA-4 is switched on. This outcompetes CD28-B7 = signal block
What is peripheral ignorance and how is a form of tolerance?
• Antigens are sequestered in organs that are not accessible to the immune system • There is a physical barrier between the self-antigen and the lymphoid system Ø Blood Brain Barrier Ø Testis Ø Anterior chamber of eye
How does regulation play a role in peripheral tolerance?
- Active suppression involving regulatory T cells (Treg) cells
- Antigen specific
- Extremely potent effects
Antigen specific
Whats a factor that determine the Tolerogenicity of Self Antigens?
T-cell activation that occurs in the absence of innate immunity or inflammation tends to trigger peripheral tolerance
What happens to autoreactive B cells?
B-cells that recognize self antigens in the absence of T- cell help die by apoptosis or become anergic
Why would the T cell signal be absent in B cell autoreactive anergy?
T cell for that antigen may already be anergic
Describe peripheral tolerance to low reactive B cells
B-cells that recognize self antigens with low affinity are prevented from responding by inhibitory receptors (CD22)
What are the two types of t regs?
1) Natural T regs
2) Inducible T regs
What is a Treg?
A population of T cells whose function is to suppress immune responses and maintain self tolerance
What generates each population of Tregs?
- Natural Tregs
• Generated by recognition of self antigen in the thymus (central tolerance) - Inducible Tregs
• Generated by recognition in the peripheral lymphoid organs (peripheral tolerance)
What receptors do Tregs express?
• CD4+
Marker used to distinguish CD4+ T cells from CD8+ T cells
Binds MHC Class II receptor
- CD25 HIGH
CD25 is the a chain of the IL-2 receptor, binds IL2
What transcription factors do Tregs express?
Express FoxP3, transcription
factor
Ø FoxP3 is a specific marker for Tregs (intracellular)
ØBinds the promoter region of genes that regulate T-cell function
Whats essential for the generation and maintenance of Tregs?
CD25 and FoxP3 are essential to generation and maintenance of Treg cells
IL2
Give one example of treg function;
- Inhibit T-cell activation
Remember: B7-CD28 co-stimulus needed for activation of T-cells via APC interaction
Tregs express CTLA-4 which binds B7 on APC and inhibits activation
Give a second example of treg function;
- Inhibit T-cell effector functions
Production of IL-10 and TGF-b
• Inhibitory cytokines that can inhibit all surrounding autoreactive T-cells
What happens if there is Treg dysfunction?
Mutations in FoxP3 result in a very rare and fatal autoimmune disorder (IPEX)
Whats the importance of Tregs in cancer?
- Normally Tregs make up ~4% circulating CD4+ T cells
- In tumor microenvironment Tregs can make up 20-30% CD4+ T cells
- Tregs suppress T effector function and natural immune response to tumour antigens
- High levels of Tregs associated with poor outcomes in a variety of cancers
What are the types of B cells?
B1 and B2 (conventional, derived from bone marrow)
What are B1 cells?
B-1 B cells are a distinct B-cell population that are initially
derived in the fetal liver
Whats special about B1 cells?
Ø Express limited repertoire of V genes (dont undergo somatic hypermutation)
Ø Part of the innate immune response
Ø Found in large numbers in peritoneal and pleural cavities
What are the properties of B1 cells?
“Natural antibodies”
◦ Produce IgM without help from T-cells
◦ Commonly react with bacterial polysaccharides (e.g. S. pneumoniae capsular polysaccharide) and self-antigens (apoptotic debris)
◦ Tend to be polyspecific
What are the functions of B1 cells?
- B-1 cell IgM have a key role in the clearance of apoptotic cells
- The clearance of dying cells an essential responsibilities of the immune system
(prevents uncontrolled autoimmunity) - B-1 IgM recognize neoepitopes on the apoptotic cell membrane
