L18- Tolerance and immune regulation

Question 1

What do Pattern Recognition Receptors do? (in innate immunity)

Answer 1

Recognise molecular patterns on microbes and potential dangers.
Recognise PAMPs & DAMPs

Question 2

Is self-reactivity normal in a healthy immune system?

Answer 2

Yes. But normally restrained by mechanisms of tolerance. These mechanisms:

• limit the production of self-reactive T and B cell clones.
• prevent unwanted destructive responses by any clones that are produced.

Question 3

What is self-tolerance?

Answer 3

Failure to respond to intrinsic self-antigens.

Can also develop tolerance to external antigens like harmless non-self antigens and therapeutically relevant antigens.

Question 4

How do you get self-tolerance?

Answer 4

It is acquired, not inherited.

Non-identical twin calves with a common placenta became tolerance of each other.

Question 5

How is tolerance established?

Answer 5

As a series of checkpoints.
1. Central tolerance: primary lymphoid organs: removal of highly self-reactive clones during lymphocyte development in bone marrow and thymus. (not absolute process)
2. Peripheral tolerance: in peripheral organs, 2ndary lymphoid organs.
Multiple mechanisms limit reactivity against self and harmless antigens in the periphery.
(Lack of t cell help for b cells, t cells different mechanisms)

Question 6

Central tolerance in B cells

Answer 6

Development of B cells in bone marrow.
1st the rearrangement of the heavy chain. Until you have a meuw heavy chain transiently expressed at surface with he surrogate alpha chain.
This is first check point. antigen-independent.
Then the first tolerance check point- if you have IgM on surface. The question being asked at this checkpoint is: Does the receptor bing to self antigens in the bone marrow?

Question 7

What is the fate of the B cell determined by?

Answer 7

Interaction with self-antigen in the bone marrow.
This interaction is influenced by:
-the concentration of antigen and it’s ability to cross-link surface receptors.
1. No self-reaction=b cell matures with Igm Igd on surface.
2. High affinity of cross-linking so multivalent self molecule= dangerous so will signal clonal deletion or receptor editing.

Question 8

How does receptor editing happen?

Answer 8

Keeps RAG genes stay on. And can get recombination at the light chain locus. Between the flanking V and the flanking J. So delete out the exon and try another one. Can continue until you have a light chain that does not cross link, or until you run out of V and J segments, at which point the cell dies.

Question 9

low-affinity non-cross-linking self molecule

Answer 9

.

Question 10

What are the 4 scenarios of immature B cells?

Answer 10

1. No self reaction-> matures
2. Multivalent self molecule-> clonal deletion or receptor editing.
3. Soluble self molecule-> unresponsive so dies rapidly
4. Low-affinity non-cross-linking self molecule-> Mature B cell- clonally ignorant

Question 11

What are the stages of T cells in development?

named according to expression of CD4 and/or CD8

Answer 11

1. Early thymocyte
2. Double negative thymocytes (neither)
3. Double positive thymocytes (both CD4 and CD8 expressed)
4. Single positive thymocytes. (either CD4 or CD8 expressed).

Question 12

Do T cells recognise antigen directly?

Answer 12

No they recognise processed antigen presented as peptide by MHC complexes.
TCRs interact with both the peptide and the MHC.

Question 13

During T cell development, TCR gene rearrangement can give rise to the following clonal scenarios:

Answer 13

1. T cells that fail to make a functional TCR=useless
2. TCR that cannot recognise self-MHC molecules=useless
3. TCR that recognises self-MHC; self-antigens too strongly=harmful
   (these are all removed)
4. TCR recognises self-MHC AND does not bind self-antigens too strongly=USEFUL 2% make it through

Question 14

What is the first checkpoint in T cell development?

Answer 14

(remember- Beta chain similar to antibody heavy chain, alpha chain looks like light chain). Beta chain rearrangeing first with the DJ etc. Quality checkpoint- if you fail to make the beta chain, the cell is useless and will die by apoptosis.

Question 15

Where do the T cells develop in the thymus?

Answer 15

Different developmental stages occur in different regions of the thymus.
This facilitates different selection criteria at different checkpoints.

Question 16

What is the second checkpoint of TCR?

Answer 16

Positive selection.
Can the rearranged double positive recognise self MHC? If so, it can survive. Gets a survival signal and moves into the medulla region and develops into single positive.
If it can’t. It may be able to recover by editing, otherwise it dies. If it can;t recognise self MHC it will die after 3-4 dies.

Question 17

What is the 3rd checkpoint of TCR?

Answer 17

Negative selection.
Does the double positive recognise self MHC + self peptide too strongly?
If they do they could be harmful and are deleted during negative selection

Question 18

How are antigens not normally expressed in the thymus presented for test binding?

Answer 18

Medullary Epithelial Cells express a transcription factor called AIRE (Autoimmune Regulator)-> causes promiscuous expression of genes not normally expressed in the thymus.

Question 19

Affinity hypothesis of T cell selection

Answer 19

If TCR is non-functional and you get no binding then T cells die.
If TCR binds self-antigen too strongly it’s potentially harmful and T cell dies.
In the middle of these-TCR binding is sufficient but not too strong these cells are useful so they survive.
Also another set- which are binding a bit too strongly but not as dangerously strong as the top ones. These are (natural/) thymic T reg (Foxp3 positive cells) which are useful so survive.

Question 20

Which T cells which make it out of the thymus?

Answer 20

1. CD4+ (Foxp3+tTreg)
2. CD8+ effector cells (CTLnaive)
3. CD4+ effector cells (Thnaive)
   These last 2 can be activated and skewed to different functions

Question 21

What determines T cell activation?

Answer 21

The context in which they see their antigen.
3 signals:
1. antigen-specific activation signal (TCR/MHC:pep)
2. co-stimulus from dendritic cells
3. cytokines (determine which way skew differentiation)

Question 22

What do B cells need t cells for?

Answer 22

B cells need T cell help to mount an antibody response

Question 23

What is peripheral tolerance in B cells due to?

Answer 23

Mainly due to lack of T cell help.
The antigen is picked up at site of inflammation. The dendritic cell rushes back to the lymph node and shows the antigen to a t cell. If t cell recognises this antigen, the t cell is activated. migrates to boundary with b cells. Meanwhile in B cell area, the antigen has drained through the lymph, recognised by B cell. Takes up antigen and presents antigen on b cell. migrates to T cell/b cell boundary. The activated helper t cell recognises the antigen presented by B cell. And will give b cell signals to help activate it into plasma cell. However if you have a self antigen that gets back to lymph node, you will not get T cell help so B cell won’t get activated into plasma cell.

Question 24

How are naive T cells activated?

What happens when there is no co-stimulation?

Answer 24

Antigens must be presented on a DC in an activation context (co-stimulation) to intitiate naive T cell activation.
Presentation in absence of danger (no co-stimulation) is Tolerogenic -> generates either anergy or regulation.

Question 25

If you get signal 1 only what happens?

Answer 25

Signal 1 alone renders a T cell anergic. It is unresponsive and cannot respond to antigen.
e.g. antigen encountered in the absence of danger

Question 26

Peripheral induced Treg (pTreg)

Answer 26

Driven by signal 3.
If you get Ag+TGFbeta signal-> foxp3+ pTregs

If you get Ag+IL10 signal-> Foxp3- Tr1.

Question 27

What so thymic derived natural Tregs and peripheral derived induced Tregs recognise?

Answer 27

1. Thymic-derived Treg (Foxp3+) recognice self antigen.

2. Peripheral-derived Treg (foxp3+ and foxp3-) recognise self antigen and also harmless non-self antigen.

Question 28

How do regulatory T cells work?

Answer 28

We're not completely sure.
Some different ideas:
1. produce anti-inflammatory cytokines.
2. Modulate dendritic cells.
3. Outcompete effector T cells for resources e.g. IL2.
4. Directly kill T cells.
5. Exosome transfer of miRNAs.

Question 29

How did they find that different parts of your body are different immunologically?

Answer 29

The gut is more tolerant to things. american indians ingested small amounts of poison ivy to become tolerant to it. But the same amount on the skin at first causes massive allergic rxn.

Question 30

Immune privilege

Answer 30

-usually enclosed by a physical barrier,
low MHC I, rich in suppressive cytokines e.g. TGFbeta and express FasL.
e.g. brain, eye, testis,uterus.
Grafts placed in these sites are not rejected and antigens placed in these sites do not elicit destructive immune responses.

Question 31

What happens when immune privilege is broken e.g. in the eyes?

Answer 31

Trauma to one eye releases antigens from the eye. Released antigen carried to lymph nodes and activates T cells. Effector T cells return and attack both eyes!

Question 32

How do cancers survive in the body?

Answer 32

They induce immune suppression and become privilege sites themselves, so are protected from the immune system