lecture 7

Question 1

What is T cell tolerance?

Answer 1

random TCR (α/β) gene arrangement that leads to T cells expressing TCR that:
a: fail to recognise self-MHC (useless)
b: recognise self-MHC + peptide generated from Ag present in the thymus (potentially dangerous)
c: recognise self-MHC + “any other” peptide not present in thymus (potentially useful)

a die by neglect
b and c are expanded by positive selection
b are eliminated by negative selection
c survive

Question 2

Why does b survive positive selection but die via negative selection?

Answer 2

b can recognise self-MHC so survives positive selection
binds self-MHC too well so dies via negative selection

Question 3

Why does c survive over a and b?

Answer 3

it has a population with medium affinity for self-MHC, so should not give an autoimmune response but includes cells that are capable of responding to self-MHC when it contains peptides derived from Ag not present in thymus

Question 4

What is AIRE?

Answer 4

-AIRE: autoimmune regulator gene; transcription factor involved in central T-cell tolerance

-Highly expressed in thymic medullary epithelial cells
-Allows the expression of many tissue-specific Ag in the thymus - hence negative selection/deletion of T cells that recognise these Ag
-Patients with AIRE deficiency have major autoimmune syndromes

Question 5

what is B cell tolerance?

Answer 5

random Ig gene rearrangement leads to many B cells potentially expressing self-reactive BCRs
Autoreactive B cells are negatively selected/deleted (in bone marrow)
B cells get a second chance to re-arrange self-reactive BCR or they rearrange another light chain (receptor editing)

Question 6

What is receptor editing?

Answer 6

new light chain may remove self-reactivity

Question 7

What can binding of self antigen by immature B cells lead to?

Answer 7

Death/editing or anergy
Leave slightly self-reactive but with low levels of BCR so not considered a risk

Question 8

What is anergy?

Answer 8

When self-reactive T or B cells become nonreactive without a costimulatory molecule

Question 9

How can T cells be made anergic?

Answer 9

T cells that are reactive can be silenced
T cells need to see signal 1 and coregulatory molecules before being regulated
Unregulated macrophages do not deliver a co-stimulatory signal to T cells recognising a non-bacterial antigen

Question 10

What is immunological tolerance?

Answer 10

many Ag are not presented at sufficient levels to activate T cells

Question 11

Are B cell responses, T cell dependent?

Answer 11

Many cell responses are
If Ag specific T cells are absent/tolerant no help in available -> no antibody response

Question 12

How do regulatory T cells show tolerance?

Answer 12

CD4+ T cells subset that suppress immune responses crucial for preventing autoimmune responses
Arise in thymus from T cells with high affinity receptors for self Ag
When they become activated they turn other t cells off

Question 13

What can a deficiency in regulatory T cells lead to?

Answer 13

deficiency of regulatory T cells leads to severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) very serious autoimmune condition

Question 14

Which cytokines are produced by regulatory T cells and what do they do?

Answer 14

IL-10 and TGF-β inhibit other self-reactive T cells

Question 15

What are B cells that secrete IL-10 crucial for?

Answer 15

preventing autoimmunity

Question 16

Why is regulation of immune responses important?

Answer 16

To ensure responses continue only for as long as they are needed
To minimise collateral (tissue) damage
To ensure responses are qualitatively appropriate for the specific pathogen

Question 17

What are the different CD4+ T cell subtypes and what are their roles?

Answer 17

CD4+ Th1 -> activation of macrophages, NK cells, cytotoxic T cells
CD4+Th2 -> promote responses mediated by eosinophils and mast cells; role in antibody responses, especially IgE
CD4+Th17 -> promote responses against fungi
CD4+Treg/Breg -> suppress unwanted responses
CD4+Tfh -> specialised Th found in GC to help B cells

Question 18

How do CD4+Th1 cells activate macrophages?

Answer 18

via secretion of cytokines
express CD40L which binds CD40 on macrophage

Question 19

How do CD4+Th1 cells kill chronically-infected macrophages?

Answer 19

Fas ligand/Fas induce apoptosis
released bacteria destroyed by healthy macrophage -> other cells can then kill the pathogens

Question 20

What is CD4+Th17 and what is its role?

Answer 20

recently identified subset of CD4+ T cells
secrete IL-17
function to recruit neutrophils early in fungal infections also implicated in autoimmune disease

Question 21

Are CD4+Treg cells a single population?

Answer 21

single population

Question 22

What cells make up CD4+Treg?

Answer 22

CD4+CD25+
Some CD8+ T cells have Treg activity

Question 23

Where do CD4+Treg arise from?

Answer 23

in the thymus nTreg or from circulating T cells in the peripheral tissues (iTreg)

Question 24

What is the mode of action of CD4+Treg cells?

Answer 24

secretion of suppressive cytokines
TGF-β, IL-10

IL-10 inhibits APC function

Question 25

How do you know whether CD4+tH1 or CD4+Th2 response?

Answer 25

The type of Th response is influenced by the cytokines that are present when T cells are activated - signal 3

Question 26

What are the key cytokines involved in naïve T cell activation by APC?

Answer 26

IL-12 and IFN-γ play a key role in induction of Th1 responses
IL-4 important doe induction of Th2 responses

Question 27

What is the impact of the cytokines present when naïve T cells are activated?

Answer 27

TGF-β, IL-10 - Treg cells
IL-21, ICOS - follicular helper T cells
IL-6, IL-17 - Th17 cells
IL-2, IFN-γ - Th1 cells
IL-4, IL-5 - Th2 cells

Question 28

What does polarisation of CD4+ T cell responses cause?

Answer 28

Th1 cytokines - promotes commitment to Th1, inhibit development of Th2,Th17
Th2 cytokines - promote commitment to Th2, inhibit development of Th1, Th17
Th17 cytokines - promote commitment to Th17 cytokines, inhibit development of Treg
Treg cytokines - inhibit Th1,Th2,Th17 responses

Question 29

How do Treg cells allow a successful pregnancy?

Answer 29

Stops rejection of baby which has antigens from father as the tregs turn off the rejection

Question 30

What is the importance of polarised responses?

Answer 30

ensures correct responses for different types of pathogens
can go wrong may lead to allergy (excessive Th2)
control of autoreactivity/pregnancy