B & T cell development & mechanisms of immunological tolerance

Question 1

What is Bone structure and contain ?

Answer 1

Bone marrow structure is dynamic & complex containing Hematopoietic stem cells that differentiate into many cell types

Question 2

B-cell development takes place?

Answer 2

Entirely in bone marrow

Question 3

T cell progenitors begin ?

Answer 3

In bone marrow & complete development in thymus

Question 4

What in the bone marrow provide support & growth

factors for lymphocyte development ?

Answer 4

Stromal cells and thymic

epithelial cells

Question 5

Hematopoiesis stages are defined by ?

Answer 5

Cell-surface markers, transcription factor expression & receptor gene rearrangements

Question 6

Central tolerance of T cells in thymus ?

Answer 6

Positive selection: MHC restriction

AND negative selection

Question 7

Central tolerance of B cells in bone marrow ?

Answer 7

No need for MHC restriction

Only negative selection

Question 8

B Lymphocytes derive from?

Answer 8

Hematopoietic stem cells in the bone marrow

Question 9

B-cell development begins by?

Answer 9

Rearrangement of the heavy-chain locus

Question 10

The pre-B-cell receptor tests for ?

Answer 10

Successful production of a complete heavy chain and signals for the transition from the pro-B cell to the pre-B cell stage

Question 11

Pre-B-cell receptor signalling inhibits ?

Answer 11

Further heavy-chain locus rearrangement and enforces allelic exclusion

Question 12

Pre-B cells rearrange the ?

Answer 12

Light-chain locus and express cell-surface immunoglobulin.

Question 13

Immature B cells are tested for?

Answer 13

Autoreactivity before they leave the bone marrow – via central tolerance

Question 14

B Lymphocytes that encounter self antigens for the first time in the periphery are ?

Answer 14

Eliminated or inactivated - via peripheral tolerance

Question 15

B cell development ?

Answer 15

1st checkpoint: no more Heavy-chain gene rearrangements
- Allelic exclusion enforced
2nd checkpoint: Repeated attempts at Light-chain
rearrangements
Central Tolerance: B cell tested for self-reactivity (negative selection) before leaving

Question 16

Negative selection purges B cells that are self-reactive?

Answer 16

3 different mechanisms:

1. Receptor editing of V & J genes Light chain
2. Anergy (inactivation)
3. Clonal deletion (apoptosis)

Question 17

What do Immature B cells arriving in the spleen do ?

Answer 17

Turn over rapidly and require

cytokines and positive signals through the B-cell receptor for maturation and long-term survival

Question 18

T-cell progenitors originate in?

Answer 18

The bone marrow, but all the

important events in their development occur in the thymus

Question 19

Commitment to the T-cell lineage occurs in the thymus following ?

Answer 19

Notch Signalling

Question 20

Where do T cells proliferate ?

Answer 20

Extensively in the thymus, but most die there

Question 21

Successive stages in the development of thymocytes are marked by ?

Answer 21

Changes in cell-surface molecules

Question 22

Thymocytes at different developmental stages are found in ?

Answer 22

Distinct part of the thymus

Question 23

T cells with α:β or γ:δ receptors arise from ?

Answer 23

A common progenitor

Question 24

Successful synthesis of a rearranged β chain allows?

Answer 24

The production of a pre-T-cell receptor that triggers cell proliferation and blocks further β-chain gene rearrangement

Question 25

T-cell α-chain genes undergo?

Answer 25

Successive rearrangements until positive selection or cell death intervenes

Question 26

Only thymocytes whose receptors interact with self peptide:self MHC complexes can ?

Answer 26

Survive and mature

Question 27

Positive selection acts on?

Answer 27

A repertoire of T-cell receptors with inherent specificity for MHC molecules

Question 28

Positive selection coordinates?

Answer 28

The expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the T cell

Question 29

Thymic cortical epithelial cells mediate ?

Answer 29

Positive selection of developing thymocytes

Question 30

T cells that react strongly with ubiquitous self antigens are deleted ?

Answer 30

In the thymus – this is negative selection and is driven most efficiently by bone marrow-derived antigen-presenting cells

Question 31

Thymic epithelial cells express?

Answer 31

High MHC I & II

Question 32

Developing T cells “browse” possible ?

Answer 32

Self-peptide/MHC complexes on thymic epithelial cells

Question 33

What does Transcription factor AIRE (autoimmune regulator) permit ?

Answer 33

Expression of hundreds of self antigens

Question 34

Positive selection detrmines?

Answer 34

Expression of either CD4 or CD8

Question 35

Negative selection of T cells?

Answer 35

TCRs bind too strongly so negative selection (deletion) occurs

Question 36

Positive selection of T cells?

Answer 36

TCRs bind “just right” so it progresses to single-positive stage - These cells are MHC restricted

Question 37

T cells specific for self-antigen are removed in the thymus by negative selection via DC?

Answer 37

Tissue-specific proteins are expressed in on thymic dendritic cells & participate in negative selection: 1. Strong binding leads to apoptosis 2. Intermediate binding by Tregs 3. No binding but can bind MHC by periphery

Question 38

Autoimmune regulator (AIRE) protein induces ?

Answer 38

- Expression of tissue-specific proteins in thymic cells | - New T cells can be screened against these antigens safely in the thymus

Question 39

Most new T cells will die because ?

Answer 39

The signals from MHC:TCR are not strong enough (neglect)

Question 40

Some T cells will be positively selected because ?

Answer 40

MHC:TCR signals generate strong enough survival signals. From these cells, some will be negatively selected if the bind too strongly to MHC/self antigen. A small subset of these with slightly weaker interaction will become Tregs

Question 41

3 fates of peripheral T cells when they react strongly to self-antigen ?

Answer 41

1. Negative selection by Apoptosis – Activation Induced Cell Death AICD - usually as a result of repeated antigen stimulation (evolved to deal with repeatedly meeting ‘self’ antigen in the periphery via Fas-FasL) 2. A small population might become Anergic – due to a lack of co-stimulation. Normally during immune response, APCs will upregulate co-stimulation via pattern recognition. CTLA-4 rather than B7 induces anergy 3. Tregs keep potentially self-reactive cells in check

Question 42

Explain the exposure of sequestered antigens ?

Answer 42

Some antigens never appear in thymus but can be later released into the circulation & potentially treated as foreign

Question 43

Underlying cause of autoimmunity can be through?

Answer 43

A fault in T-cell education & tolerance in the thymus

Question 44

Loss of tolerance: neoantigens?

Answer 44

A normal self antigen becomes modified & appears as a non-self antigen e.g. Infections, burns, uv exposure, drugs e.g. penicillin

Question 45

Loss of tolerance: Molecular Mimicry ?

Answer 45

Microbial antigens can have protein sequences that exactly | match human self antigens