Immunological tolerance Flashcards
a) define immunological tolerance
b) describe central tolerance
a) a state of unresponsiveness to substances or tissues capable of eliciting immune responses
b) seen with positive and negative selection. All T cells that exit the thymus can bind to MHC with peptide. Only the strongest binders are purged by negative selection. The T cells that leave the thymus will still exhibit some level of self-reactivity, so it is essential to have additional mechanisms of tolerance to avoid activation of T cells in response to self antigens and commensal flora. This is achieved through AIRE.
Medawar’s neonatal tolerance experiment
Medwar proposed that there is a developmental stage at which exposure to an antigen will lead to immunological tolerance, rather than immune activation. Exogenous cells transferred in the first few days of life are tolerised, but not if they are transferred later
Describe AIRE, and effect of AIRE deficiency
AIRE ensures that almost all tissue-specific antigens are also expressed in the thymus. AIRE proteins control the process of thymic medullary cells expressing tissue-specific proteins, and lead to the deletion of tissue-reactive T cells.
AIRE deficiency syndrome (APECED/APS-1) - individuals suffer from a wide range of autoimmune symptoms: hypoparathyroidism, adrenal gland insufficiency, hepatitis.
Central tolerance of B cells
Autoreactive B cells are purged or silenced. The deletion of B cells specific for autoantibodies occurs in the bone marrow. Anergy induction of the B cells mostly occurs in the spleen. Some autoreactive B cells can also undergo secondary recombination of light chain genes (receptor editing)
Five types of peripheral tolerance
Ignorance. Split tolerance. Anergy. Treg suppression. T cell exhaustion
Peripheral tolerance - ignorance
Certain tissues such as the brain, eyes, and testes are largely devoid of infiltrating lymphocytes and aren’t drained by lymphatics. These are referred to as immune privileged sites. This may also be maintained by TGFβ and FASL expression. The immune privilege can be broken, which leads to pathological immune responses.
The fetus in pregnancy is essentially in an immune privileged site. Only the placenta shares circulation with the mother, hence the mother’s T cells cannot reject the foetus itself. The placenta lacks convential MHCI and doesn’t express MHCII, so it is less visible to CD8 and CD4 T cells.
Peripheral tolerance - split tolerance
B cells require T cell help. If an autoreactive B cell presents autoantigen, but there is no T cell that recognises what is presented, the the B cell doesn’t undergo class switching or affinity maturation and will only secrete low-affinity IgM, which causes minimal harm. Therefore, the requirement for a cognate T cell, recognising the same antigen, dramatically reduces the chance of inappropriate development of high-affinity IgG antibodies.
How dendritic cells become competent to stimulate T cells
At the initial site of infection, dendritic cells detect the pathogenic antigen, take it up and move to a draining lymphatic vessel to enter the lymph node, where they display the antigen in T cell areas. Therefore, it is important the the dendritic cells are able to detect and display only pathogenic antigens, not self or commensal non-self.
In the peripheral tissue, immature dendritic cells recognise PAMPs and become activated (when PAMP binds to TLR). TLR signalling induces several things: i) CCR7 is induced, which enhances the processing of pathogen-derived antigens, and also mediates the migration of the DC to the draining lymph node. ii) B7 (CD80/CD86) is highly expressed on the DC (for binding to T cell CD28) iii) pathogenic antigen is displayed on MHC by the DC to present to naive T cells.
Peripheral tolerance - anergy
T cells require two signals to be activated. If they only recieve one signal, this induces anergy (a state of unresponsiveness)
Mechanisms of regulation by Treg
i) They secrete inhibitory cytokines - TGFβ and IL-10 inhibit self-reactive T effector cells
ii) They can induce cytolysis - granzyme A/B is secreted to induce cytolysis, especially in apoptotic T effector cells
iii) Thet can disrupt metabolism in T effector cells, causing their death
iv) Most importantly, they can target dendritic cells to inhibit their maturation - they express high levels of CTLA4, which binds to dendritic cell B7 more strongly than regular CD28. This binding of CTLA4 can remove B7 from the dendritic cell, meaning it can no longer activate further naive T cells.
IPEX
A lethal X-linked autoimmune disease caused by mutations in Foxp3. Foxp3 is the transcription factor that induces production of Treg. Therefore, mutations in Foxp3 means that Treg production is significantly decreased, hence there is no regulation of self-reactive T effector cells, causing autoimmunity. This highlights the importance of peripheral tolerance, especially the role of Treg cells.
Peripheral tolerance - T cell exhaustion
Chronic activation of T cells by an antigen that persists leads to T cell exhaustion, as the T cells are clearly insufficient to fight the pathogen, hence activating them is a waste of resources. Exhausted T cells express the receptor PD1, which binds to PDL1, a widely expressed ligand including on macrophages and dendritic cells, which provides a suppressive signal to the T cell. Additionally, the exhaused T cell will express CTLA4, so when this binds to dendritic cell B7, will prevent the DC from activating further T cells reactive to the same antigen.
CTLA1 and PD1 in cancer therapy
Cancer cells often display PDL1 to inhibit the action of T cells to the cancer cell antigen. Additionally, cancer cells rely on T cells expressing CTLA4 to prevent further activation of T cells that are reactive against the cancer cell’s neoantigens (as they can be perceived as self).
Therefore, anti-CTLA4 and anti-PD1 drugs have been introduced to prevent this inhibition of T effector cells, to upregulate the killing of the tumour cell. Ipilimumab is an anti-CTLA4 drug, and nivolumab is an anti-PD1 drug.
However, whilst these drugs have been effective at producing an anti-cancer response, they can also induce autoimmunity and innappropriate immune responses against commensal flora, hence further development must be made.
