March 26th (Exam 3) Flashcards
Why do 80% of T cells make a positive rearrangement of the beta chain?
How many chances does the beta chain have for rearrangement?
Because the Beta chain has 2 constant segments and their associated D and J segments meaning that it has two tries per homologous chromosome.
Per cell, the beta chain has 4 chances for rearrangement.
A cell makes a positive rearrangement of the beta chain right away and forms a pre-T-cell receptor, effectively becoming a pre-T cell.
What does the signalling through the pre-T-cell receptor impart?
- We gets suppression of the RAG1 and RAG2 genes effectively shutting down the rearrangement machinery imparting allelic exclusion at the beta chain locus.
- That cell is signalled to proliferate and along with this expression of both CD4 and CD8.
What happens after proliferation of the pre-T cell?
The DP thymocytes become smaller and the recombinational machinery is turned back on for the alpha, gamma and delta chain loci.
What does the rearrangement of the alpha chain (productive or not) do?
What must happen to make it IMPOSSIBLE for the cell to become a gamma-delta T cell?
It deletes the delta loci within the alpha loci on chromosome 14
A rearrangement of the alpha loci must be at least attempted at both loci.
What happens once a productive alpha chain rearrangement is made?
It is made and translocated to the ER where it is tested for its capacity to bind to the beta chain.
What are the two checkpoints that we have talked about in T-cell development?
- Assembly of pre-T-cell receptor
- Assembly of TCR
What happens if the TCR assembly is successful?
The cell is signalled to survive and proceeds to positive selection.
What happens if the alpha chain does not appropriately assemble with the beta chain?
More rearrangements are tried until a functional alpha chain is made or the rearrangements are exhausted and the cell dies.
What is the advantage of expressing both types of co-receptors on the surface of DP thymocytes?
It allows the cell the option to use either coreceptor depending on whether its T-cell receptor is more fitted to recognizing peptide antigens presented by self MHC class I or II molecules.
Describe the locations of major events in the formation of DP thymocytes in the Thymus.
- The progenitor cells enter at the cortical-medullary junction.
- They move outward in the cortex becoming committed to the T-cell lineage
- Assuming beta chains rearrange first, we then get a checkpoint
- Proliferation causes the pre-T cells to express CD4 first then CD8, turn machinery back on
- Assuming alpha chain is made, another checkpoint occurs where we see the assembly of the TCR (or more rearrangement/apoptosis)
What specifically grants the TCR the ability to interact with MHC molecules?
The specificities built into the V gene segments of the TCR.
What benefit does the rearrangement of TCR genes have in recognizing MHC molecules?
Well it confers each person’s repertoire with insane amounts of receptors that might bind the thousands of isoforms of MHC I and II molecules that exist within the human population.
How often does a DP Thymocyte have the receptor needed to interact with the particular forms of MHC isoforms expressed by that individual?
Only about 2% of the time.
What do we call the process by which a small subpopulation of DP thymocytes are selected for by interaction with complexes of self peptides and self MHC molecules present on the surface of cortical epithelial cells?
Positive Selection
The particular MHC isoform that positively selects the DP thymocyte is the the one becomes restricted.
What does this mean?
This means that the T-cell and all of its progeny will only recognize their specific peptide antigen only in the context of that particular isoform.
If an alpha chain that a pre-T cell makes is productive and results in a alpha-beta T cell receptor that can interact with a self MHC molecule, the cell is then signaled to turn off recombinational machinery and proliferate.
What about if it just can’t find a self MHC molecule that fits?
Explain how receptor editing (alpha chain) happens and why it is possible.
If the T cell receptor doesn’t find an MHC that works, it is allowed to “try on” some alpha chains that might work better and it can do this for like 3-4 days.
There are a lot of V and J segments in the alpha chain loci.
How is it possible for 1/3 of all mature alpha-beta T cells to carry two DIFFERENT T cell receptors?
Why is it actually negligible
Well, because the alpha chain is not subject to allelic exclusion it can have rearrangement at both copies and can express two TCRs that have the capacity to undergo positive selection.
This actually doesn’t really matter because the chances that two TCRs can both be activated by peptides presented by self MHC molecules is very low.`
How do we get mature T cells that only express either CD4 or CD8?
Positive selection via the kinase Lck.
What are the bare lymphocytes syndromes classified as?
What are they?
Immunodeficiency diseases.
This is when the person either fails to express MHC Class I or II molecules on lymphocytes/thymic epithelial cells.
What is the process by which T cells whose antigen receptors bind too strongly to complexes of self peptides and self MHC molecules are selected and wiped out?
Why even wipe them out?
Explain the process, where it happens, which cells are involved etc.
This is called negative selection.
Those T-cells who fit that criteria are problematic because they are potentially autoreactive and could cause autoimmune disease.
When a T-cell binds too tightly to a dendritic cell (from progenitor cell) or bone marrow derived macrophage within the cortical-medullary junction or in the cortex, it is signalled to die.
How does negative selection encompass all the tissue specific proteins that a mature NAIVE T-cell might run into?
It uses a specific transcription factor called AutoImmune REgulator that causes the transcription of hundreds of other tissue-specific proteins by the epithelial cells of the thymus medulla.
These proteins are then taken up by MHC complexes and used in negative selection.
What happens if a T-cell escapes and is still autoreactive?
There are other mechanisms like the B-cell that render it anergic when it is going off not in the presence of an infection.
What are all the functions of CD4 T-cell helper?
- Activate Macrophages
- Activate B cells
- Suppress the response of autoreactive CD4 T cells
Explain what T(regs) are and how they do what they do.
What markers (and other stuff) are unique to T(regs)?
These are cells that can suppress the response of autoreactive CD4 T cells.
They do this by having TCRs that recognize self peptides, and by interacting with other T-cells that are contacting the SAME Antigen Presenting Cell.
They have FoxP3 transcriptional repressor protein and cell surface marker CD25
