B & T cell development & mechanisms of immunological tolerance Flashcards
What is Bone structure and contain ?
Bone marrow structure is dynamic & complex containing Hematopoietic stem cells that differentiate into many cell types
B-cell development takes place?
Entirely in bone marrow
T cell progenitors begin ?
In bone marrow & complete development in thymus
What in the bone marrow provide support & growth
factors for lymphocyte development ?
Stromal cells and thymic
epithelial cells
Hematopoiesis stages are defined by ?
Cell-surface markers, transcription factor expression & receptor gene rearrangements
Central tolerance of T cells in thymus ?
Positive selection: MHC restriction
AND negative selection
Central tolerance of B cells in bone marrow ?
No need for MHC restriction
Only negative selection
B Lymphocytes derive from?
Hematopoietic stem cells in the bone marrow
B-cell development begins by?
Rearrangement of the heavy-chain locus
The pre-B-cell receptor tests for ?
Successful production of a complete heavy chain and signals for the transition from the pro-B cell to the pre-B cell stage
Pre-B-cell receptor signalling inhibits ?
Further heavy-chain locus rearrangement and enforces allelic exclusion
Pre-B cells rearrange the ?
Light-chain locus and express cell-surface immunoglobulin.
Immature B cells are tested for?
Autoreactivity before they leave the bone marrow – via central tolerance
B Lymphocytes that encounter self antigens for the first time in the periphery are ?
Eliminated or inactivated - via peripheral tolerance
B cell development ?
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
Negative selection purges B cells that are self-reactive?
3 different mechanisms:
- Receptor editing of V & J genes Light chain
- Anergy (inactivation)
- Clonal deletion (apoptosis)
What do Immature B cells arriving in the spleen do ?
Turn over rapidly and require
cytokines and positive signals through the B-cell receptor for maturation and long-term survival
T-cell progenitors originate in?
The bone marrow, but all the
important events in their development occur in the thymus
Commitment to the T-cell lineage occurs in the thymus following ?
Notch Signalling
Where do T cells proliferate ?
Extensively in the thymus, but most die there
Successive stages in the development of thymocytes are marked by ?
Changes in cell-surface molecules
Thymocytes at different developmental stages are found in ?
Distinct part of the thymus
T cells with α:β or γ:δ receptors arise from ?
A common progenitor
Successful synthesis of a rearranged β chain allows?
The production of a pre-T-cell receptor that triggers cell proliferation and blocks further β-chain gene rearrangement
T-cell α-chain genes undergo?
Successive rearrangements until positive selection or cell death intervenes
Only thymocytes whose receptors interact with self peptide:self MHC
complexes can ?
Survive and mature
Positive selection acts on?
A repertoire of T-cell receptors with inherent specificity for MHC molecules
Positive selection coordinates?
The expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the T cell
Thymic cortical epithelial cells mediate ?
Positive selection of developing thymocytes
T cells that react strongly with ubiquitous self antigens are deleted ?
In the thymus – this is negative selection and is driven most efficiently by bone marrow-derived antigen-presenting cells
Thymic epithelial cells express?
High MHC I & II
Developing T cells “browse” possible ?
Self-peptide/MHC complexes on thymic epithelial cells
What does Transcription factor AIRE (autoimmune regulator) permit ?
Expression of hundreds of self antigens
Positive selection detrmines?
Expression of either CD4 or CD8
Negative selection of T cells?
TCRs bind too strongly so negative selection (deletion) occurs
Positive selection of T cells?
TCRs bind “just right” so it progresses to single-positive stage
- These cells are MHC restricted
T cells specific for self-antigen are removed in the thymus by negative selection via DC?
Tissue-specific proteins are expressed in on thymic dendritic cells & participate in negative selection:
- Strong binding leads to apoptosis
- Intermediate binding by Tregs
- No binding but can bind MHC by periphery
Autoimmune regulator (AIRE) protein induces ?
- Expression of tissue-specific proteins in thymic cells
- New T cells can be screened against these antigens safely in the thymus
Most new T cells will die because ?
The signals from MHC:TCR are not strong enough (neglect)
Some T cells will be positively selected because ?
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
3 fates of peripheral T cells when they react strongly to self-antigen ?
- 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)
- 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
- Tregs keep potentially self-reactive cells in check
Explain the exposure of sequestered antigens ?
Some antigens never appear in thymus but can be later released into the circulation & potentially treated as foreign
Underlying cause of autoimmunity can be through?
A fault in T-cell education & tolerance in the thymus
Loss of tolerance: neoantigens?
A normal self antigen becomes modified & appears as a non-self antigen e.g. Infections, burns, uv exposure, drugs e.g. penicillin
Loss of tolerance: Molecular Mimicry ?
Microbial antigens can have protein sequences that exactly
match human self antigens
