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31 Cards in this Set

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What do DP and thymocytes undergo in order to form the self-MHC restricted, self-tolerant mature T cell repertoire?
positive and negative selection
What is positive selection?
selection of T cells that are able to interect with self-MHC molecules.
Only those that can function in self-MHC restricted responses are kept.
What is negative selection?
getting rid that have too much affinity for self-peptides/self-MHC complexes
What does irradiation do to the mice?
destroys all lymphocytes and bone marrow progenitors
what happens when we introduce bone marrow cells from a mouse with a certain MHC genotype into a an irradiated mouse of another MHC genotype?
all the bone marrow-derived cells (dendritic cells, lymphocytes, macrophages) of the recipient will be of the donor MHC type, but all other cells are of recipient MHC genotype
Will an immune response be detected in an irradiated MHCb mice injected with MHCa bone marrow?
No, because their periphery APCs only express MHCa. An immune response will be detected if MHCb APCs are injected at time of immunization
What is responsible for the positive selection of developing T cells, MHC restriction?
Thymic Stroma
What does the introduction of transgenes that contain rearranged alpha and beta chain-genes do in mice?
it inhibits rearrangement of endogeneous alpha and beta genes (just like in BCR transgenic mice)
What type of thymocytes can survive and mature in transgenic mice?
Those that express a TCR able to interact with self-MHC complexes
What happens in the absence of positive selection?
Cell death
What determines which co-receptor a mature T cell will express?
The specificity of the TCR for self MHC
Which DP T cells will mature?
Those expressing a co-receptor that binds the same MHC molecules as the TCR
MHC class II deficiency:
have CD8+ T cells and very few abnormal CD4+ T cells
MHC class I deficiency:
have CD4+ T cells and very few abnormal CD8+ T cells
Bare lymphocyte syndrome:
absence of MHC molecules in humans
How is the expression of CD8+ or CD4+ determined?
all thymocytes upregulate CD4
- CD4+:
~if cell is selected by MHC II, signal is sustained in part by Lck
~induction of Th-POK transcription factor
~differentiation along the CD4 pathway and loss of CD8 expression
-CD8+:
~if cell is selected by MHC I
~there is no further signaling via Lck because CD4 is not ligated
~no induction of Th-POK
~differentiation along CD8 pathway
~loss of CD4 expression and upregulation of CD8 expression
Which thymic stromal cells mediate positive selection of developing thymocytes?
the cortical epithelial cells
How is negative selection of developing thymocytes mediated?
When thymocytes interact with specific peptide/self-MHC on cells in the thymus
What was the experimental evidence found involving the HY transgenic TCR mice?
Male mice that carried the transgenes for this TCR, transgenic thymocytes die at the DP stage and no mature transgenic T cells are found in the periphery, but in females (who don't express the HY protein) the transgenic T cells mature normally
Conclusion: thymocytes that carry a TCR specific for self-peptide/self-MHC molecules are deleted in the thymus
What happens to T cells that recognize "tissue-specific" self-Ags which are not expected to be expressed in the thymus?
They are many "tissue-specific self-Ags expressed in the thymus, and their expression is controlled by AIRE (autoimmune regulator)
What do mutations in AIRE result in?
Disease called autoimmune polyglandular syndrome type 1
Which other type of cells can mediate negative selection?
Thymic epithelial cells
How does the engagement of the TCR to self-peptides/self-MHC complexes can lead to survival of thymocytes during positive selection and cell death during negative selection?
2 mechanisms have been suggested:
- interactions that lead to positive selection much include more TCR specificities than those that lead to negative selection (otherwise all positively selected T cells would be eliminated during negative selection)
- consequences of the interactions between TCR and self-peptides/self-MHC complexes that occur during positive selection and negative selection must be different (since one leads to cell death and the other to survival)
Strength of Signal Hypothesis:
What does the consequence of interaction btwn TCR and s-p/s-M complexes depend on?
On the strength of the signal delivered by the TCR
What does the stregnth of the signal depend on?
On the affinity of the TCR fro the s-p/s-M complexes and the density of the spsM on thymic cortical epithelia
What type of signals do the thymocytes receive in order to be positively or negatively selected?
- those receiving a weak signal that drives survival are positively selected
- those receiving a strong signal inducing cell death are negatively selected
What type of signal is more often seen in thymocyte selection?
since more TCRs have low affinity for spsM complexes and most self-peptides are expressed at low density, more cells are positively selected rather than negatively selected
Qualitative Signaling hypothesis:
What distinguishes positive from negative selection?
- quality of signal delivered through the TCR (therefore unlike the strength of signal hypoth. changes in density of s-p/s-M would not affect quality of signal)
How many mature thymocytes are exported in the periphery everyday?
1 - 2 x 10^6
What do the naive mature T cells need to survive in the periphery?
- contact with self-peptide/self-MHC complexes
- cytokines (e.g. IL-7)