March 24th (Exam 3) Flashcards
Two types of T-cells develop from what?
Name the two types.
They develop from a common T-cell precursor.
The two types are alpha-beta T cells and gamma/delta T cells.
Where do T cells originate?
Where do they mature?
They originate in the bone marrow like B-cells
They mature in the Thymus (primary lymphoid organ that sits just superior to the heart)
Why is the thymus considered a primary lymphoid organ?
Because its primary purpose is the maturation of T-cells (not fighting infection)
It does not receive lymph from other tissues or participate in lymphocyte recirculation.
What is the only way in and the only way out of the thymus?
The blood.
What is all in the thymus?
Describe its structure.
- Thymocytes - immature T cells
- Thymic stroma - network of epithelial cells
The thymocytes are embedded in the network of thymic stroma.
Thymus has two main parts:
Closely-packed cortex
Inner, less dense medulla
What is the embryonic thymus (rudimentary) called?
From which germ layer do the following cells come from?
- Epithelial cells of Cortex
- Epithelial cells of Medulla
Thymic Anlage
The epithelial cells of the cortex come from ectoderm, while the epithelial cells of the medulla come from the endoderm
What happens to the thymic anlage?
Where do the dendritic cells of the thymus hang out?
The rudimentary thymus becomes colonized with progenitor cells of the bone marrow that become the thymocytes and dendritic cells.
The dendritic cells hang out in the medulla.
Other cells from the bone marrow are macrophages that also spend most of their time within the medulla but can be scattered in the cortex.
Describe the general physical path of T-cell progenitors in the thymus.
They enter the thymus at the junction between the cortex and the medulla. As they differentiate, they move out through the cortex to the subscapular region, and then progressively to the inner cortex and the medulla.
The idea of the thymus degenerating a year after birth is called what?
What happens to the area which once held the full thymus?
involution of the thymus
Fat gradually claims the area
What do we call the disease in which the thymus fails to develop?
Are B cells still possible?
Adaptive immunity?
This is called DiGeorge syndrome
B-cells are still present but there is no adaptive immunity.
Why does involution of the thymus not grossly impair T-cell immunity?
Because once the T-cell repertoire is established, they seem to be long-lived, self-renewing or both.
What are the progenitor cells like when they enter the thymus?
Are they committed to the T-cell lineage?
How do we know yes/no?
They are progenitor cells and they are not committed to the T-cell lineage, made clear by the presence of CD34 (marker) and CD44 (adhesion) on their cell surface.
How do the progenitor cells become committed to the T-cell lineage?
What is the most important cytokine that we talked about?
How long does this take?
How do we know?
They interact with the thymic stroma cells that signal to them to divide and differentiate.
The stromal cells secrete Interleukin 7 that binds to the IL7 receptor on the progenitor cells.
It takes about a week before they start lacking any stem cell markers and are committed to the T-cell lineage as seen by the presence of CD2 and CD5
When does the rearrangement of the T-cell receptor genes start?
When the cell has committed to the T-cell lineage.
When an cell that has just committed to the T-cell lineage, it is called double negative.
Why?
Because it neither expressed CD4 or CD8 (only the previously mentioned CD2 and CD5)
What keeps a Thymocyte from differentiating into a B cell?
Explain the process.
Notch 1
This is a membrane associated receptor that binds its ligand on the thymic epithelium.
Once it binds its ligand, the intracellular part of the notch 1 receptor on the thymocyte gets cleaved and makes its way to the nucleus.
Here, it displaced repressive transcription factors from the promoters and recruits activators that prevent problematic differentiation.
Where do both types of T cells from?
The DN Thymocyte.
What are the first gene arrangements that happen for a DN thymocyte?
The gamma the delta and the beta - all at roughly the same time.
What happens if gamma and delta rearrange and make functional T-cell receptor chains before beta?
It will commit to the gamma-delta T cell.
After help by the CD3 signalling complex it signals for rearrangement to stop (eat up RAG1,2 and stop transcription)
It can then basically leave the thymus in the blood and enter the circulation.
What if the beta rearranges and forms a functional beta chain before gamma and delta?
It gets incorporated into a molecule called the pre-T-cell receptor, favoring the alpha-beta T cell, but not committing it.
Rearrangement will stop and the cell will proliferate, expressing both CD4 and CD8
Then rearrangement of the other chains resumes and the rearrangement/production competition starts up again.
If the alpha chain is made, cell commits to alpha-beta T cell
If the gamma/delta receptor is made first, it commits to the gamma/delta lineage.
What do we call cells that express both CD4 and CD8?
Double Positive Thymocytes.
What happens to cells that fail to make productive T-cell receptor gene arrangements?
What proportion of the thymocytes that fall into this category?
They are signalled to die and then get phagocytized by the bone marrow derived macrophages on the thymic cortex.
98% of the thymocytes will die like this.
Explain the rearrangement that needs to be done for each chain.
alpha
beta
gamma
delta
- alpha - just one positive VJ rearrangement
- beta - two positive VDJ rearrangements
- gamma - just one positive VJ rearrangement
- delta - two positive VDJ rearrangements
What is the more frequent outcome of the competition of gene rearrangements?
What happens?
The beta chain gets made, it gets translocated to the ER and is tested for its capacity to bind to an invariant polypeptide call pT-alpha (acting like a surrogate alpha chain)
