Flashcards in The Life of a T Cell- Forming and Educating Deck (57):
What is the first step of T cell maturation in the thymus?
VDJ rearrangements of the beta chain followed by VJ rearrangement of the alpha chain.
What does the AB TCR need to associate with in order to recognize HLA-I and HLA-II antigen presentation?
CD4 or CD8 coreceptors
CD4 participates in TCR interactions with HLA complexes of what class?
CD8 participates in TCR interactions with HLA complexes from what class?
CD4- class II
CD8- class I
What does the ab TCR heterodimer non-covalently associate with to intracellularly signal?
CD3 (epsilon/delta, gamma/epsilon, zeta/zeta)
What kind of T-cell recognizes antigen presented by CD1 complexes?
iNK T cells recognize glycolipids complexed in CD1.
What do gamma/delta TCR recognize and what is their function?
Recognize: lipids AND peptides
Function: cytokine release
What does CD4 SP recognize and what is its function?
Recognize: MHC II/antigen
Function: help B macro make antibody response, releases cytokines, stimulate macrophages
What does CD4 Treg recognize and what is its function?
Recognize: MHC II/peptide
Function: suppress T cells that may be autoimmune
What does CD8 SP recognize and what is its function?
Recognize: HLA I/antigen
Function: Kill pathogenic cell
What does iNKT cell recognize and what is its function?
Recognize: glycolipid in a CD1 complex
Function: release cytokines
What does the i stand for on iNKT cell and why?
Invariant because there are very limited VDJ recombinations
What cells make up the thymic architecture?
1. epithelial cells
2. mesenchymal cells
3. hematopoietic cells --> thymocytes
What cell is missing from the thymus?
Interactions between what two cells is responsible for the 3-D meshwork structure of the thymus?
1. Epithelial cells
If a person is lymphopenic, what will their thymus resemble?
the epithelia will be striated instead of a 3D meshwork and it will look like layers of skin
In what syndrome does a person lack a thymus? What is result of lacking a thymus?
DiGeorge Syndrome results in a lack of peripheral T cells
The developmental fate of the T cell in the thymus depends on the specificity of the TCR for ______________.
the peptide/HLA complex recognized
When the TCR engages peptide/HLA class II on a thymic epithelial cell, dendritic cell or other APC WEAKLY, what occurs?
It matures into a CD4 SP
When a TCR engages HLA class I/peptide on a thymic epithelial cell or dendritic cell weakly, what occurs?
The T-cell develops into a CD8 SP
What is meant by SP?
Single positive- one coreceptor is expressed
What are the four major subpopulations of T cells in the thymus?
Which subpopulation are the majority of thymocytes in the thymus?
DN- double negative
DP- double positive (both CD4, CD8 receptors)
The majority of thymocytes are DP
How do the T cell subpopulations differ from the thymus and the lymph node?
Thymus- all four subpopulations, mostly DP. No B cells
Lymph node- CD4SP, CD8SP and B cells
When hemopoietic stem cells enter the thymus, what cell do they become?
How many stages are there for DN cells in the thymus?
In what stage does TCRb VDJ rearrangement occur?
VDJ rearrangement occurs in DN2-DN3
What cytokine is a crucial growth factor that enables T cells to expand from DN to DP?
What is the function of IL-7?
It is a growth factor that allows DN to expand to DP
What is thymopoiesis?
The progression of T cells in the thymus from DN to DP to CD4SP and CD8SP
In what part of the thymus does stem cell-> DN-> DP?
In what part of the thymus does DP-> CD4SP or CD8SP?
from the cortex to the medulla
What structures are present on the cell surface of a DP thymocyte?
1. TCRab with CD3 structures
What occurs in T cell maturation if there is an unsuccessful arrangement of TCRb locus?
The cell arrests at DN3 stage and dies
What is the T cell called after one TCRb locus makes a protein product?
What 3 events occur when this is achieved?
pre-TCR which sends intracellular signals to:
1. terminate further B-locus rearrangements
2. Re-express RAG1/2 to initiate VJ rearrangment for the alpha chain
3. Coordinately express CD8 and CD4
Do NK T cells develop before or after VDJ recombination?
What happens if a DP T cell does not encounter an HLA/peptide complex in the thymus?
it dies by neglect
What is the general idea of positive selection of T cells?
If the abTCR interacts with weak affinity to an HLAself/self-peptide complex, the cell will survive and become the appropriate SP cell.
What is the general idea of negative selection of T cells?
If the abTCR interacts with a peptide/HLA complex with high avidity, it will be deleted or killed because this means that it is too highly reactive to a selfHLA/self-antigen and may cause autoimmune problems.
What is the fate of the majority of DP T cells?
They will undergo programmed cell death because there is no signal to induce anti-apoptotic genes
Why does a weak avidity interaction of a TCR with selfHLA/self-antigen allow the cell to survive and convert to a single positive?
The interaction induces anti-apoptotic genes and the cell can overt cell death
In the transgenic mouse studies, when the female mouse was injected with male tissue, there was an expansion of what type of cell?
CD8 SP T cells to destroy the male tissue
In the female transgenic mouse injected with male tissue, her lymph nodes were isolated and her CD8 Tcells were removed and cloned. If they took the DNA for the TCR of this CD8 T cell, what would they see?
What would happen if this DNA was injected into a new mouse?
The DNA was already rearranged so all the T cells produced in the new strain would have the same TCR that binds male tissue presented in an MHC I complex.
What did experimentation of transgenic mice show in regard to positive selection?
A self-peptide derived from a self-protein was involved in CD8SP T cell development.
Originally the TCR was educated with HY male peptides and recognized them in the context of MHC I. The experimentors knocked out TAP so the mouse couldn't make MHC I. When then added back self-peptides structurally related to the HY male peptides, CD8 SP T cells were able to be made again.
The process of positive selection involves and education to recognize _____________ derived from ________________ expressed in the _________________ of the thymus.
self-peptides, self-proteins, epithelial tissues
If the TCR binds 15-20AA self-peptides, what HLA class does it recognize and what will the cell develop into?
HLA II and the cell will develop into CD4 SP T cell.
If the TCR recognizes an 8-10 AA self-peptide what HLA class does it recognize and what wil the cell develop into?
HLA I and the cell will develop into CD8 SP T cell
What determines whether positive selection or negative selection will occur in the thymus?
The strength and duration of the interaction between the TCR and the self-HLA/self-peptide complex
What type of signal induces positive selection in the thymus?
What type of signal induces negative selection in the thymus?
Strong and short signals
What transcription factor forces tissue specific antigens to be expressed in the thymus?
What is AIRE? What does it allow tolerance of?
AIRE is a transcription factor that forces the expression of tissue specific antigens in the thymus.
This allows T cells to be tolerant of self-peptides expressed in different organs
Where is the AIRE transcription factor expressed?
thymic epithelial cells
What would a knockout mutation of AIRE cause?
positively-selected T cells that become reactive to self-peptides in the peripheral tissue (autoreactivity)
What is a TREC?
T cell receptor excision circle: it is the DNA that is excised from the genome during VDJ rearrangement
Why are TRECs important?
1. They are used as a genetic screen for immunodeficiencies in newborns
2. They are used to monitor thymic output after chemoablative procedures
What receptor do positively-selected cells in the thymus express?
What is this receptor required for?
Shingosine-1-phosphate receptor is required for the T cell to enter the blood where high levels of shingosine1P circulate
What is shingosine-1-phosphate?
A molecule in the blood that attracts the shingosine-1-phosphate receptor on the positively-selected cells from the thymus (CD4SP, CD8SP) to allow them to circulate
What does the drug FY720 do?
It is an immunsuppressant that blocks the T cell from egressing into the blood from the thymus and lymph node