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114 Cards in this Set
- Front
- Back
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What happens to immature B cells after they leave the bone marrow?
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Go to the spleen where they migrate into the white pulp
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What is the white pulp?
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Lymphoid tissue of the spleen
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Where are naive B cells localized to in the spleen and other lymphoid organs?
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Follicles
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What happens in the spleen when mature B cells are involved in an immune response?
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They develop germinal centers into follicles
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What happens to the mature B cells that are in follicles but are not involved in an immune response?
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They're pused outwards and form the Mantle Zone
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Where are the T cells localized to in the spleen?
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PALS
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What does the marginal zone contain?
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Special subset of mature B cells
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What type of cells (other than B cells) do the follicles also contain?
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Follicular Dendrtitic Cells (FDC): specialized stromal cells
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Are FDC's leukocytes?
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No, they're not derived from bone marrow precursors
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What are Interdigitating Dendritic cells?
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Lymphoid and myeloid dendritic cells
Both come from a common bone marrow derived myeloid precursor |
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Where are the interdigitating dendritic cellslocated
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T cell area
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What controls the precise location of B, T and dendritic cells?
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Chemokines (chemoattractant cytokines)
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What attracts T cells?
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-CCL19
-CCL21: =>Secreted by stromal cells of the T cell zone of the spleen (CCL21) => Secreted by Interdigitating dendritic cells (CCL19 and CCL21) |
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What do the chemokines CCL19 and CCL21 bind to?
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CCR7
Receptor expressed by T cells |
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What attracts B cells?
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CXCL13
->Secreted by FDC |
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What does the B cell chemokine (CXCL13) bind to?
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CXCR5
->This is expressed by mature B cells |
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What is the migration pattern of B cells? What may account for this?
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B cells migrate to the T cell zone and then to the follicle
Might do this bcause they express low levels of CCR7 |
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How many pro-, pre-, immatur and mature B cells are there?
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Pro-B cells: 80x10^6/day
Pre-B cells:35x10^6/day Immature: 10-20x 10^6/day Mature: 1-2x10^6/day |
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Why would a pro-B cell not become a pre-B cell?
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Failure to make a pproductive heavy chain gene rearrangement
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Why would pre-B cells not becom immature B cells?
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Failure to make a productive light chain gene rearrangemet
Tolerance induction: clonal deletion of B cells reactive to multivalent self-Ag |
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What do self-tolerant, immature B cells express?
What is its half-lie? |
High IgM
Low IgD Half life: ~ 3 days |
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What happens with the immature and long-lived mature B cells that are already established?
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Competition btw immmature and mature B cells that are already established in the peripheral B cell pool for survival signals provided by the follicle
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Which might have easier access to the follicle: im/mature B cell?
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Mature B cells might have easier access to the follicles because mature B cells have undergone phenotypic changes
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What is the half life of a long-lived, mature, naive B cell?
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1-2 months
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What do mature B cells express?
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Low IgM
High IgD |
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What role does Syk play in B cells?
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Ptn Tyrosine kinase
Involved in signal to BCR -> No Syk, problem, block between immature B cell and mature B cell |
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What happens in Syk KO mice?
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Have immature B cells but can't develop mature B cells
->Signal through the BCR may be required for the final B cell maturation |
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What is the evidence that there may be positive selection of B cells for final maturation?
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BCR repertoire of mature B cells is enriched for certain Ag specificities compared witht the immature B cell population
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What do mature B cells require for survival?
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1) Signalling through their BCR
2) May also need survival signals from the follicle through which they recirculate every few days |
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What does BAFF-receptor/BAFF do?
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Provide an important signal for follicular B cell surival
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What happens in BAFF-R KO mice?
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Have mainly immature B cells and few long lived peripheral B cells
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What are B-1 cells?
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Their development precedes that of conventional B cells (B-2 cells)
Don't reside in follicles |
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Compare and contrast B1 and B2 cells.
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B1: CD5+/-
B2: No CD5 B1: High IgM (even when mature) B2: Low IgM (when mature) B1: NO IgD B2 High IgD, even when mature B1: location: peritoneal, pleural cavities B2: located in lymphoid organs |
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What are the 2 hypotheses for the origina of B1 cells?
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1) Distinct lineage from a unique precursor cell that is active durin the fetal life. Fetal liver -> B1 cells. Adult bone marrow -> mostly B2
2)Differentiate from the same precursor that could give rise to B2 cells |
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What determine's whether a precursor will become B1 or B2?
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BCR specificity
-> Commitment to B1 or B2 requires a selection step |
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What maintains B1 cells?
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Self-Ag or non-self Ag normally expressed by the bacterial flora
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What are marginal zone B cells?
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Unique subset of mature B cells
Live in marginal zone of spleen, not follicles |
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What common features are there between marginal zone B cels an B1 cells?
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High IgM
Low IgD CD23 low/- Restricted BCR repertoir biased towards common bacterial Ag and self-Ag |
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What is a difference between marginal zone B cells and B1 cells?
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Don't express CD5+
Have high CD21 |
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For B1 cells, what are the:
Isotypes secreted? Responses to carb Ag? Responses to ptn Ag? Recruitment for T-cell help? |
IgM>>IgG
Responds to carb Ag May respond to ptn Ag Does NOT need T cell help |
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For conventional B2 cells, what are the:
Isotypes secreted? Responses to carb Ag? Responses to ptn Ag? Recruitment for T-cell help? |
IgG > IgM
May respond to carb Ag Does respond to ptn Ag Does require T cell help |
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For marginal zone B cells, what are the:
Isotypes secreted? Responses to carb Ag? Responses to ptn Ag? Recruitment for T-cell help? |
IgM>IgG
does respond to carb Ag Does respond to ptn Ag Sometimes requires the help of T-cells |
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What do natural Ab do?
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Highly cross reactive and bind with low affinity to both microbial and self Ag
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What role do B cells play in adaptive response?
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Contribute to early phase of adaptive response
Little contribution to adaptive response to most Ptn Ag Strongly contribute to Ab response vs carbohydrate Ag |
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What types of B cell is a major source of IgM in non-immunized mice?
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B-1 cells
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Where are T cell precursors generated?
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Bone marrow
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Where do some T cell precursors migrate to?
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Thymus
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What do T cell precursors that migrate to the thymus express?
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Notch1 receptor
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What does signalling through Notch1 receptor do?
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Instructs the progenitor cell to develop to theT-cell lineage rather than the B or NK cell lineage
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What supports the other cells in the thymus?
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Embryonic tissue: 3rd pharyngial + 3rd branchial cleft => Thymic anlage (epithelial cells)
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What is the embryonic tissue colonized by?
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T cell precursor
Dendritic cells Macrophages |
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Describe the lobules of the thymus.
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Each lobule has:
Outer cortical region: thymus cortex Inner medulla |
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What are the developing T-cell (thymocytes) embedded in?
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Thymic stroma (cortical and medullary epithelial cells)
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At what point in life is the T-cell production by the thymus the greatest?
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Before puberty
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What happens after puberty?
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The thymus begins to shrink and the production of new T cells is lower in adults (but it continues throughout life)
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What happens if the thymus of an adult is removed?
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Do NOT lose immunity
Once the Tcell repertoire has been established, immunity can be sustained without the production of large numbers of new T cells |
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Why does removing the thymus from aults not have drastic effects on the immune system?
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T cells have very long half lives and can proliferate as required
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What induces precursor cells of the thymus to differentiate?
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The thymic stroma
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What happens to mice with nude mutations?
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Thymic epithelium fails to differentiate
-> DiGeorge syndrome in humans |
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What happens to SCID mice (similar to RAG deficient mice)?
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Mutation in DNA-dependent ptn kinase, cannot join DNA at the junctions between gene segments encoding the V region (can't rearrange properly, so can't make BCR/TCR, don't get B/T cell development)
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How are the principle stages of T-cell development distinguished from each other?
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Differential expression of
-TCR α and β chains -CD3 complex -Co-receptor ptns CD4 and CD8 |
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What do the earliest T cell population in the thymus express?
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None of the prvious molecules
Double negative thymocytes (negative for CD4 and CD8) |
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What do these double negative thymocytes give rise to?
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-γδ T cells (minority, don't express CD4/CD8 even when mature)
-αβ T cells (majority) |
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What happens to the double-negatice thymocytes in the αβ T cell lineage?
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They'll give rise to double positive thymocytes (express both CD4 and CD8 cells)
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What do double positive T cells first express? Later express?
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First express pre-TCR (β chain with a surrogate α chain)
Later express a TCR and most of them will die |
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Which T cells will survive?
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Those that can interact with self-MHC molecules will survive
Then they lose expression of either CD4 or CD8 (single positive thymocytes) |
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Where are single positive thymocytes exported to?
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Exported to the periphery as CD4+ or CD8+ mature T cells
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What do precursor T cells express once they have differentiated into one of the 2 lineages?
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CD3+
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Do γδ T cells express a TCR?
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No, only αβ T cells express a TCR once they are double positive
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How are the antigen-receptor in B and T cells generated?
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Through the rearrangement of V,D and J genes
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Where do these reaarangements occur for T ceels?
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2 different genetic loci
-alpha chain and beta chains of TCR loci OR -gamma chain and delta chain loci |
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Is this rearrangement precise or imprecise? Why?
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Very imprecise
Not all the V-(D)-J reaarangements can make a complete in frame DNA sequence that can be translated into a protein |
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What are productive and nonproductive rearrangements?
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Productive: successful rearrangements
Nonproductive: Unsucessful rearrangements that don't result in a functional protein |
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How many loci rearrange at the ame time?
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Just 1
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What rearranges first?
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Beta chain locus
D-> J Then V-> D J |
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What happens if these rearrangements are productive?
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Express beta chain protein which will bind to a surrogate alpha chain that the T cell produces
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What happens when these 2 chains come together?
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Form a receptor that is expressed at the cell surface (pre-TCR)
->Expression of pre-TCR creates intracellular signals that stop rearrangement at the beta locus and induce cell division (cells that make non-productive rearrangements apoptose) |
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What happens next?
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Rearrangement at the alpha chain locus
V -> J |
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What happens if the rearrangement at the alpha chain is productive?
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Alpha chain pairs with beta chain and the thymocyte expresses an antigen-receptor at the surface (TCR)
->cells that make a nonproductive rearrangement apoptose |
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What are the differences in B and T cell development?
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1) In B cells: productive rearrangement at the light chain locus leads to expression of a BCR that signals the cessation of rearrangement at the light chain loci
In T cells, rearrangement at the alpha chain locus contiues unless there is signalling to positively select for the TCR that is expressed 2) 2 different lineages of T cell (γδ and αβ T cells) are made |
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How many DN (double negative) stage divided into?
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4 stages
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What is expressed in the first DN stage?
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Kit+, CD44+, CD25-
α and β chain genes in germline configuration |
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What is expressed in the 2nd DN stage?
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Kit+, CD44+, CD25+
Dβ -> Jβ rearrangement starts |
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What happens in DN3?
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Kit-low, CD44-low, CD25+
Dβ -> Jβ rearrangement continues Vβ-> DJβ rearrangement starts |
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When can cells progress to DN4 stage?
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If β chain associates with a surrogate α chain (pre-T cell α) => pre-TCR expression
(Productive rearrangement) |
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What is required to express a pre-TCR?
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rearranged β chain + pre-Tcell α + CD3
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What does expression of a pre-TCR do?
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Proliferation
Arrest of furthr β chains gene rearrangement Expression of CD4 and CD8 |
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What is expressed in DN4?
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Kit-, CD44-, CD25-
Proliferation,arrest of β chain gene rearrangement |
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What happens in DP (double positive)?
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Expression of CD4 and CD8 and pre-TCR
Vα -> Jα rearrngement starts Expression of a TCR |
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What is the positive selection event that takes place?
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Only thymocytes that express a TCR that can interact with self-MHC molecules will continue their differentiation
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What is single positive expression?
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Expression of CD4 OR CD8 and TCR
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What happens after the α:β:CD3 surface expression?
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Selective events begin (only in T-cells, not B-cells)
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What are similarites between B and T cell rearrangement?
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TCR α-chain is similar to Ig k and λ light chains:
-No D segments -Rearranged only after their partner receptor-chain gene has been expressed -Repeated rearrangements can rescu on-productive joins (the number of Jα genes is greater, .: the # of possible succesful Vα to Jα rearrangements at both alleles is greater) |
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What is the major difference between the rearrangement of the TCR α-chain and the light chain of the BCR?
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The TCR α-chain locus continues to rearrange even if there is expression of a TCR
.: can have in frame rearrangements at the α chain locus on BOTH alleles (BCR rearrngement stops once a BCR is produced) |
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How many α chains can be produced in a developing T cell? Why?
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Several
The different α chains when expressed with the same β chain will be tested for self-MHC recognition |
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When does gene rearrangement stop for T cells?
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When an α-chain paired with the β-chain leads to expression of a TCR that can recognize self-MHC molecules => POSITIVE selection
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Is the TCR α-chain locus subject to allelic exclusion?
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No
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What is the advantage of the T cells being able to express several different α chains during positive selecion?
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Increases the production of useful T cells (without this mechanism, many more thymocytes would die)
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Can T-cells express more than one TCR?
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Yes, they can express 2 TCRs
-> a consequence of continuous rearrangement at tTCR α-chain locus |
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Why doesn't expression of dual TCR specificity challenge the clonal selection theory?
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Only 1 of the TCRs will be able to recognize antigenic peptides presented by self-MHC molec (only 1 of the TCRs will be able to interact with an MHC)
->a single specificity is expressed by the T cell |
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Can γδ T cells have productively rearranged β chain genes?
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Yes
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Do αβ T cells have rearranged γ-chain genes?
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Yes but they're mostly out of frame
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When do the two types of T cells diverge from the common precursor?
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After certain gene rearrangements have already occured
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When do the β, γ and δ loci undergo rearrangements in the DN thymocytes?
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Simultaneously
->Productive rearrangements of the γ and δ gene leads to the expression of a γδ TCR |
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What do DN3 cells express?
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γδ TCR and pre-TCR that contains a β chains and the surrogate pTα chain
(the B chain genes rearrange at the same time as the γδ chain rearrangements and pairs with te surrogate α-chain to make a pre-TCR) |
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What happens if the DN thymocyte eceives a signl through its γδ TCR?
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The cell switches off expression of the β-chain and commits to the γδ lineage
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What happens if the DN thymocyte gets a signal through its pre-TCR?
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-Turn off expression of γ and δ chain genes
-Stop morearrangement at the β-chain gene locus -Proliferation is induced -Expression of CD4 and CD8 is induced -Rearrangement at the α-chain is initiated (get α/β) |
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What are the first T cells to appear during embryonic development?
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γδ T-cells
(They first appear in discrete waves. In each wave, the γδ T-cells populate distinct sites) |
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Where do the T-cells go during the first wave? The second wave?
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1st: Epidermis: dendritic epidermal T cells (dETCs)
2nd: reproductive epithelium |
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What kind of receptors are expressed by the earlywaves of γδ T cells?
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The receptors are ~ homogenous
-All the cells in eachwave assemble the same Vγ and Vδ regions.No N-nucleotide additions (TdT is NOT expressed in these embryonic T cells) |
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What do dETCs express?
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Vγ5: most proximal V gene
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What do the reproductive epithelium T cells express?
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Vγ6 (2nd most proximal V gene)
Both dETC and reproductive epithelium rearranged γ-chains are expressed with the same rearranged δ-chain gene |
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What kind of T cells are made afterembryoni development
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αβ T-cells predominate (95% of thymocytes) and are made continuously instead of in short bursts
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Where do the γδ T cells that are made later reside?
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Lymphoid organs
->Have more diverse TCR repertoire, use several different V gene segments and have N-nucleotide additions |
