IAI - immune recognition and immune tolerance Flashcards
what is immune tolerance?
Immune tolerance prevents autoreactivity but permits approproate anti-pathogen responses.
What is thymic education?
- The thymocytes from the bone marrow are seeded into the thymus and it is at this site that they start to express a functional T-cell receptor.
- It’s T-cell receptor genes are rearranged and paired together.
- Cells with a functional alpha-beta T cell receptor start to express both of the core receptors, CD4 and CD8.
- other cells die with apoptosis.
less than 1% of thymocytes that enter this education process ever actually graduate into the peripheral circulation.
what is positive selection in t-cells?
- make sure TCR able to bind to MHC with at least weak affinity
- occurs at thymic cortex
- affinity for MHC11 = CD4
- affinity for MHC1 = CD8
- no affinity = dead (apoptosis)
why dont we want cells with a high affinity?
to stop auto-immunity, this is also why negative selection occurs
what is negative selection
- we eliminate T cells which have receptors with a particularly high affinity for self-peptide and self-MHC.
takes place in the thymic medulla on specialised APCs called thymic medullary epithelial cells (TMECs)
What do thymic medullary epithelial cells express?
TMECs possess transcription factors that allow them to express tissue-restricted antigens TRAs
So TMECs possess special transcription factors that allow them to express proteins which would normally only be expressed in a very restricted set of tissues.
if TMECs fail to express ______, what automimmune disease does it lead to?
TMECs fail to express TRAs ( tissue-restricted antigens) = APS type 1 (autoimmune polyglandular syndrome).
What are the 2 peripheral mechanisms of immune tolerance?
- Anergy
- Regulatory T cells
What is anergy?
- signal 1 without signal 2
- T cell remains in circulation but unresponsive to future stimulation
- APC do not express co-stimulatory molecules
why is anergy important?
- Anergy is important for tolerance to (self) antigens not expressed in the thymus.
- It is important for tolerance to (non-self) food antigens.
- Important for tolerance to commensal bacteria.
whats the role of regulatory t-cells
dedicated to controlling/suppressing effector T cells
how do regulatory t-cells alter t-cell function, and how do they alter signals?
- alter T cell function by:
- no proliferation
- no cytokine production
- alter signal by:
- reducing co-stimulation
- altering cytokine production
whats the 2 types of regulatory t-cells
nTreg
aTreg
describe Natural regulatory T cell or nTreg
‘naturally occurring’
Produced in thymus
Respond to self antigens
Protection for autoimmunity
describe Adaptive/induced regulatory T cell or aTreg
‘adaptive, i.e. induced’
Develop in periphery
Constant low level exposure to antigen
Protection from autoimmunity
Regulation of responses to food antigens
What happens to individuals lacking nTreg?
autoimmune disease developments IPEX
How does the activation of naive lymphocytes occur?
- activation occurs in lymph node
- dendritic cells migrate from tissue to local draining lymph node
- secrete chemokine + cytokines
- up regulation of adhesion molecules on high endothelial venules that line arteriole going into lymph node
- increase migration of naive T cells into lymph node
- signals allowing T cell migration out of lymph node blocked
- increase in size + cellularity of lymph node = INFLAMMATION
Outline the activation of naive CD4 + T lymphocytes (acquired response 1).
signal 1 = the MHC of dendritic cell recognises the TCR from t-cell
signal 2 = costimulation of CD28 on t-cell and CD86 on dendritic cell
signal 3 = if bacterial antigens are present the signal 3 is given by cytokine production by the dendritic cell, that instructs the T cell to polarise into the type of T cell subset, that’s good at clearing that particular bacterial infection.
if the dendritic cell has encountered intracellular pathogens like Listeria, tuberculosis, leprosy - then they will be producing IL-12 and this will drive the naive T cell towards what t-helper cell?
Th1
if the dendritic cell has encountered extracellular parasites, things like Schistosoma, trichinella then they’ll start to secrete IL-4 and this will drive the naive T cell towards the differentiation pathway towards what t-helper cell?
Th2
if the dendritic cell has encountered extracellular bacteria, things like Klebsiella then the dendritic cell will be producing TGF-Beta and IL-6 and this will drive the naive T cell down the differentation pathway to become what t-helper cell?
Th17
if the antigen presenting cell hasn’t encountered much in the way of pathogen or danger then it will actually largely be producing what?
producing cytokines such as TGF-Beta and IL-2 and IL-1 via Treg
Outline the activation of naive CD8 + T lymphocytes
- provides cytokine help with cytotoxic T cells
- allows CD8 T cell to differentiate, proliferate + gain effect of function
after how many days do cells burst out of the lymph node and migrate to the site of infection
4-6 days
Explain what happens when T cells encounter inflamed tissue.
- T cells cross into tissue
- do not find APC with complementary MHC peptide = leave and go back to lymphatics
- inflamed: find APC with specific MHC molecule
- CD4 T cells release cytokines for help
- CD8 T cell kill cell
- cleared pathogen = inflammation removed
- some T cells migrate out of inflamed tissue and laid down = maintenance of immunological memory
Explain what occurs when the infection is removed.
- the innate system is no longer activated-inflammation subsides
- antigen is cleared -the stimulus for T cells is removed
- most effector T and B are removed-death by neglect/cytokine
- Apoptotic cells are removed by macrophages
do keats quiz on Immune recognition and immune tolerance
https://keats.kcl.ac.uk/mod/lesson/view.php?id=7651858
What are 2 methods to prevent the function of Tregs?
- anti-tumour responses
- vaccination
What has been discovered in addition to PAMPs?
damage associated molecular patterns (DAMPs).
These are endogenous activators that can be produced by dead, dying or stressed cells that can also lead to activation of antigen presenting cells.
Thymic medullary epithelial cells can migrate to what type of tissue in the body
Thymic medullary epithelial cells are located in the thymic medulla and can express antigens normally only found in tissues outside the body such as liver antigens. This enables negative selection of T cells that recognise a range of self antigens, in the thymus.
difference between PAMPs and DAMPS
(Pathogen-Associated Molecular Patterns) indeed exogenous activators. trigger immune responses when recognized by the innate immune system.
(Damage-Associated Molecular Patterns) are endogenous activators. trigger immune responses when released from damaged or dying host cells.
