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78 Cards in this Set
- Front
- Back
Fate of self tolerant immature B cells: what is their trajectory?
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The immature B cells leave the Bone Marrow and reach the Spleen (where they migrate into the White Pulp - lymphoid tissue)
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Where are naive mature B cells localized in the spleen and other lymphoid organs?
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In discrete regions called follicles
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Where do mature B cells involved in an imm resp develop?
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In the germinal centers of follicles
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What happens to the mature B cells that are not involved in an imm resp?
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They are pushed outward and form the mantle zone of the follicles
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What does the marginal zone of the lymphoid organs contain?
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A special subset of mature B cells
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Where are T cells localized?
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In the periarteriolar lymphoid sheath
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What other type of cells does the follicles contain?
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Specialized stromal cells called follicular dendritic cells, which are NOT leukocytes and NOT derived from bone marrow precursors
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What does the T cell area contain?
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Interdigitating dendritic cells (lymphoid and myeloid dendritic cells - both from a common precursor)
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What controls the location of B, T and dendritic cells?
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Chemokines
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T cells are attracted by?
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CCL19 (MIP-3beta) and CCL21
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SLC secreted by?
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- stromal cells of the T cell zone of spleen - CCL21
- interdigitating dendritic cells - CCL19 + CCL21 |
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What receptor does CCL19 and CCL21 bind to?
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CCR7 expressed by T cells
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What chemokine are B cells attracted by?
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CXCL13 (BLC secreted by Follicular dendritic cells)
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What receptor does CXCL13 bind to?
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CXCR5 expressed by mature B cells
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What other receptor does the mature B cells express at low levels?
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CCR7 (that may account for their characteristic migration pattern)
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Pop. of Pro-B cells:
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80 x 10^6 /day
of which more than half will fail to make a productive heavy chain rearrangement |
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Pop. of Pre-B cells:
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35 x 10^ 6 /day
of which about half will fail to make productive light chain gene rearrangement some undergo Tolerance induction |
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Tolerance induction?
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clonal deletion of B cells reactive to multivalent self-Ag
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Pop. of Immature B cells:
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10-20 x 10^6 /day
of which some become anergic self-reactive B cells + self-tolerant immature B cells (half-life of about 3 days) |
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Pop. of Self-tolerant immature B cells:
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become mature, long-lived, naive B cells
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Pop. of mature, long-lived naive B cells
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1-2 x 10^6 /day
(half-life of about 1-2 months - IgM low, IgD high) |
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What determines the fate of an immature B cell in the periphery?
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a few things:
- a signal through BCR may be required for the final B-cell maturation (Syk signalling) - there may also be positive selection of B cells for final maturation |
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Survival of mature B cells:
What do they need to survive? |
- signalling through their BCR
- survival signals from the follicle through which they recirculate every few days |
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What is the function of BAFF-R/BAFF?
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It provides important signal for follicular 3B cell survival
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BAFF-R KO mice:
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they have mainly immature B cells and few long-lived peripheral B cells
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Mature B-cell heterogeneity:
What are B-1 cells? |
- mature B-cells that do not reside in follicles
- express CD5 - high IgM, no IgD - located in peritoneal and pleural cavities |
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Origin of B-1 cells:
what are the 2 hypotheses? |
1. there's a distinct lineage from unique precursor cell that is active during the fetal life; fetal liver produces B-1 cells while adult Bone Marrow generates predominantly B-2 cells
- they differentiate from the same precursor cell that could give rise to B-2 cells |
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What determines B-cell type commitment?
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BCR specificity determines whether a precursor will become a b-1 or in b-2 cell
(a selection step) .:Note:. B-1 cells are maintained by 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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another unique subset of mature B cells that do not reside in the follicles but in the marginal zone of the spleen
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Marginal zone B cells features:
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- IgM high
- IgD low - CD23 low/- - NOT CD5+ - CD21 high - have restricted BCR repertoire biased toward common bacterial Ag and self-Ags |
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B cell contributions:
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-early phase adaptive imm repsonse
- not as much to adapt imm resp to most protein Ag - contribute strongly to Ab response against carb Ags - B-1 cells are major source of IgM found in non-immunized mice |
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T-cell development:
Where does T-cell progenitor develop? |
Bone marrow
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Where does the precursor rearranges its T-cell precursor genes?
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Thymus
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Where does positive and negative slection of T-cell occur?
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Thymus, and then the mature T cells migrate to the peripheral lymphoid organs
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Where are the T-cells activated?
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In peripheral lymphoid organs where they encounter foreign Ags, and then they migrate to the sites of infection
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What receptor do the T-cells migrating to the thymus express?
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Notch1 receptor, which also instructs progenitor cell to develop into a T-cell
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What is the origin of the thymic epithelia?
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third pharyngial pouch + third branchial cleft => thymic anlage (rudimentary thymus)
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What cells colonize the thymic anlage?
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T cell precursors + dendritic cells + macrophages
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Describe the cell organization of the thymus.
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- Lobules, which are each divided in...
- an outer cortex and an inner medulla |
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Where are the thymocytes localized?
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in a network of epithelial cells known as the thymic stroma (cortical and medullary epithelial cells)
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Waht cells are found in the cortex?
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immature thymocytes
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What cells are found in the medulla?
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more mature thymocytes, dendritic cells and macrophages
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What does the differential distribution reflect?
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the different developmental events that occur within the 2 compartments
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How is the rate of T cell production different from before to after puberty?
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- greater before puberty
- after, thymus starts to shrink and produce less T cells |
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Is removal of thymus in adults fatal?
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No, it is not accompanied by a loss of immunity
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The crucial role of the thymic stroma:
SCID - |
these mice have a defect that prevents lymphocyte maturation.
it is similar to a RAG-deficiency, mutation in DNA-dependent protein kinase, can't join DNA at the junctions between gene segments encoding the V region |
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nude -
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these mice have a defect affects cortical epithelium
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T cell development stages:
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- DN
- DP pre-TCR - DP TCR - SP |
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1. DN (double negative thymocytes)
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- CD4 neg and CD8 neg
- will give rise to γδ T cells (minority) and αβ T cells (majority) |
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2. In αβ lineage, we then have DP pre-TCR (double positive)
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- CD4 pos and CD8 pos
- at first, β chain is with a surrogate α chain - later they express a TCR but less than 5% will survive |
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3. SP (single positive thymocytes)
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- only cells whose TCR interact with self-MHC moleucles will survive and lose expression of either CD4 or CD8
- they are then exported to the periphery as CD4+ or CD8+ mature T cells |
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Lymphocyte development:
What type of gene rearrangements occur in T cells? |
- V, D and J rearrangments occur at 2 diff loci
- α + β chains of the TCR locus OR - γ + δ chains locus |
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In what order does the beta chain locus rearrange itself ?
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D -> J
V -> DJ |
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What happens when the beta chain locus has a productive rearrangement?
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- T cell produces a surrogate α chain that is paired with the β chain (pre-TCR)
- receptor generates intracellular signals that causes cessation of the rearrangement at the locus and induces cell deivision |
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What happens when the alpha chain locus has a productive rearrangement?
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- α chain pairs with β and thymocyte expresses an Ag-receptor at the surface
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Differences between B and T cells:
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- in T cells, rearrangment at the α chain continues unless there is signalling to positively select the TCR that is expressed
- 2 different lineages of T cells are produced - T cell develop. program must control which of the 2 lineages becomes committed and ensure that the mature T cell expresses receptor components from only one lineage |
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What are the different stages of Double Negative? DN1
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- DN1: Kit+, CD44+, CD25-; α and β chain genes in germline config
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DN2:
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- DN2: Kit+, CD44+, CD25+; Dβ -> Jβ starts
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DN3:
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- DN3: Kit-low, CD44-low, CD25+; Dβ -> Jβ continues; Vβ -> DJβ starts
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DN4:
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- DN4: Kit-, CD44-, CD25-;
- proliferation - arrest of further β chain gene rearrangement (allelic exclusion) |
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DP:
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- expression of CD4 and CD8 and pre-TCR
- Vα -> Jα rearrangement starts - Expression of TCR -then we get positive selection: only thymocytes that express a TCR able to interact with self-MHC molecules will continue their differentiation |
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SP:
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expression of either CD4 OR CD8 on the TCR
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TCR α-chain gene locus:
Why is the gene comparable to the Ig kappa and lambda? |
- it has no D gene segments (only V and J)
- rearranged only after their partner receptor-chain gene has been expressed - repeated rearrangments can rescue non-productive joints (# of Jα is greater) |
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Major difference in rearrangement at the TCR α-chain:
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rearrangment at the TCR α-chain continues even if there is expression of a TCR
- it results in several different α chains in each developing T cell - gene rearrangement will stop only when an α chain paired with β chain leads to the expression of a TCR that will recognize self-MHC molecules (positive slection) |
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What are the consequences of continuous rearrangment at TCR α chain locus?
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- increase the the production of useful T cells
- increases chance of generating T cells with 2 TCRs |
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What is the trajectory of a thymocyte in the thymus?
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- DN1 (medulla)
- DN2 (cortex) - DN3 (subcapsular region) - DN4 immature DN (subcapsular region) - immature DP (cortex) - mature SP (cortico-medullary junction) |
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How does the T cell lineages diverge from their common precursor?
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after certain gene rearrangement has already occured
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How does rearrangement of γ, δ and β occur in DN?
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simultaneously -> DN3 expresses both γδ TCR and a pre-TCR
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How is one of the two TCR selected?
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signalling through either its γδ TCR or αβ TCR
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What happens if γδ TCR receives a signal?
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cell switches off expression of beta chain and commits to the gamma-delta
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What happens if the DN receives a signal through its pre-TCR?
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- expression of gamma and delta chain genes is switched off
- further rearrangement at beta gene is arrested - proliferation induced - expression of CD4/8 induced - alpha gene rearrang. begins |
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When do γδ T cell first appear?
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embryonic development, in discrete waves at first
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1st wave:
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populates epidermis (dendritic epidermal T cells - dETCs)
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2nd wave:
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populates reproductive epithelium
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What is particular about the receptors expressed by the early waves of γδ T cells?
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all the cells in each wave assemble the same Vγ and Vδ regions (no N-nucleotides additions)
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What γ and δ chains are expressed in dETCs and the reproductive epithelium?
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dETCs: Vγ5 (most proximal V gene)
reproductive epithelium: Vγ6 (2nd most proximal) Both γ chains are expressed with the same δ-chain gene |
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How is the production of T cells after the embryonic stage?
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continuous production -> αβ T cells predominate (95% of thymocytes)
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Are γδ still produce after the embryonic stage?
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Yes, they are found in lymphoid organs, have more diverse TCR repertoire (use several diff V gene segments and have N-nucleotide additions)
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