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31 Cards in this Set
- Front
- Back
What do DP and thymocytes undergo in order to form the self-MHC restricted, self-tolerant mature T cell repertoire?
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positive and negative selection
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What is positive selection?
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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. |
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What is negative selection?
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getting rid that have too much affinity for self-peptides/self-MHC complexes
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What does irradiation do to the mice?
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destroys all lymphocytes and bone marrow progenitors
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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?
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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
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Will an immune response be detected in an irradiated MHCb mice injected with MHCa bone marrow?
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No, because their periphery APCs only express MHCa. An immune response will be detected if MHCb APCs are injected at time of immunization
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What is responsible for the positive selection of developing T cells, MHC restriction?
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Thymic Stroma
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What does the introduction of transgenes that contain rearranged alpha and beta chain-genes do in mice?
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it inhibits rearrangement of endogeneous alpha and beta genes (just like in BCR transgenic mice)
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What type of thymocytes can survive and mature in transgenic mice?
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Those that express a TCR able to interact with self-MHC complexes
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What happens in the absence of positive selection?
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Cell death
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What determines which co-receptor a mature T cell will express?
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The specificity of the TCR for self MHC
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Which DP T cells will mature?
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Those expressing a co-receptor that binds the same MHC molecules as the TCR
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MHC class II deficiency:
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have CD8+ T cells and very few abnormal CD4+ T cells
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MHC class I deficiency:
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have CD4+ T cells and very few abnormal CD8+ T cells
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Bare lymphocyte syndrome:
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absence of MHC molecules in humans
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How is the expression of CD8+ or CD4+ determined?
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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 |
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Which thymic stromal cells mediate positive selection of developing thymocytes?
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the cortical epithelial cells
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How is negative selection of developing thymocytes mediated?
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When thymocytes interact with specific peptide/self-MHC on cells in the thymus
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What was the experimental evidence found involving the HY transgenic TCR mice?
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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 |
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What happens to T cells that recognize "tissue-specific" self-Ags which are not expected to be expressed in the thymus?
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They are many "tissue-specific self-Ags expressed in the thymus, and their expression is controlled by AIRE (autoimmune regulator)
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What do mutations in AIRE result in?
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Disease called autoimmune polyglandular syndrome type 1
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Which other type of cells can mediate negative selection?
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Thymic epithelial cells
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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?
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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) |
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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
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What does the stregnth of the signal depend on?
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On the affinity of the TCR fro the s-p/s-M complexes and the density of the spsM on thymic cortical epithelia
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What type of signals do the thymocytes receive in order to be positively or negatively selected?
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- those receiving a weak signal that drives survival are positively selected
- those receiving a strong signal inducing cell death are negatively selected |
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What type of signal is more often seen in thymocyte selection?
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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
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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)
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How many mature thymocytes are exported in the periphery everyday?
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1 - 2 x 10^6
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What do the naive mature T cells need to survive in the periphery?
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- contact with self-peptide/self-MHC complexes
- cytokines (e.g. IL-7) |