IAI - immune recognition and immune tolerance

Question 1

what is immune tolerance?

Answer 1

Immune tolerance prevents autoreactivity but permits approproate anti-pathogen responses.

Question 2

What is thymic education?

Answer 2

• 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.

Question 3

what is positive selection in t-cells?

Answer 3

• 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)

Question 4

why dont we want cells with a high affinity?

Answer 4

to stop auto-immunity, this is also why negative selection occurs

Question 5

what is negative selection

Answer 5

• 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)

Question 6

What do thymic medullary epithelial cells express?

Answer 6

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.

Question 7

if TMECs fail to express ______, what automimmune disease does it lead to?

Answer 7

TMECs fail to express TRAs ( tissue-restricted antigens) = APS type 1 (autoimmune polyglandular syndrome).

Question 8

What are the 2 peripheral mechanisms of immune tolerance?

Answer 8

• Anergy
• Regulatory T cells

Question 9

What is anergy?

Answer 9

• signal 1 without signal 2
• T cell remains in circulation but unresponsive to future stimulation
• APC do not express co-stimulatory molecules

Question 10

why is anergy important?

Answer 10

• 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.

Question 11

whats the role of regulatory t-cells

Answer 11

dedicated to controlling/suppressing effector T cells

Question 12

how do regulatory t-cells alter t-cell function, and how do they alter signals?

Answer 12

• alter T cell function by:
  
  • no proliferation
  • no cytokine production
• alter signal by:
  
  • reducing co-stimulation
  • altering cytokine production

Question 13

whats the 2 types of regulatory t-cells

Answer 13

nTreg
aTreg

Question 14

describe Natural regulatory T cell or nTreg

Answer 14

‘naturally occurring’

Produced in thymus

Respond to self antigens

Protection for autoimmunity

Question 15

describe Adaptive/induced regulatory T cell or aTreg

Answer 15

‘adaptive, i.e. induced’

Develop in periphery

Constant low level exposure to antigen

Protection from autoimmunity

Regulation of responses to food antigens

Question 16

What happens to individuals lacking nTreg?

Answer 16

autoimmune disease developments IPEX

Question 17

How does the activation of naive lymphocytes occur?

Answer 17

• 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

Question 18

Outline the activation of naive CD4 + T lymphocytes (acquired response 1).

Answer 18

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.

Question 19

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?

Answer 19

Th1

Question 20

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?

Answer 20

Th2

Question 21

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?

Answer 21

Th17

Question 22

if the antigen presenting cell hasn’t encountered much in the way of pathogen or danger then it will actually largely be producing what?

Answer 22

producing cytokines such as TGF-Beta and IL-2 and IL-1 via Treg

Question 23

Outline the activation of naive CD8 + T lymphocytes

Answer 23

• provides cytokine help with cytotoxic T cells
• allows CD8 T cell to differentiate, proliferate + gain effect of function

Question 24

after how many days do cells burst out of the lymph node and migrate to the site of infection

Answer 24

4-6 days

Question 25

Explain what happens when T cells encounter inflamed tissue.

Answer 25

• 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

Question 26

Explain what occurs when the infection is removed.

Answer 26

• 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

Question 27

do keats quiz on Immune recognition and immune tolerance

Answer 27

https://keats.kcl.ac.uk/mod/lesson/view.php?id=7651858

Question 28

What are 2 methods to prevent the function of Tregs?

Answer 28

• anti-tumour responses
• vaccination

Question 29

What has been discovered in addition to PAMPs?

Answer 29

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.

Question 30

Thymic medullary epithelial cells can migrate to what type of tissue in the body

Answer 30

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.

Question 31

difference between PAMPs and DAMPS

Answer 31

(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.