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78 Cards in this Set

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Fate of self tolerant immature B cells: what is their trajectory?
The immature B cells leave the Bone Marrow and reach the Spleen (where they migrate into the White Pulp - lymphoid tissue)
Where are naive mature B cells localized in the spleen and other lymphoid organs?
In discrete regions called follicles
Where do mature B cells involved in an imm resp develop?
In the germinal centers of follicles
What happens to the mature B cells that are not involved in an imm resp?
They are pushed outward and form the mantle zone of the follicles
What does the marginal zone of the lymphoid organs contain?
A special subset of mature B cells
Where are T cells localized?
In the periarteriolar lymphoid sheath
What other type of cells does the follicles contain?
Specialized stromal cells called follicular dendritic cells, which are NOT leukocytes and NOT derived from bone marrow precursors
What does the T cell area contain?
Interdigitating dendritic cells (lymphoid and myeloid dendritic cells - both from a common precursor)
What controls the location of B, T and dendritic cells?
Chemokines
T cells are attracted by?
CCL19 (MIP-3beta) and CCL21
SLC secreted by?
- stromal cells of the T cell zone of spleen - CCL21
- interdigitating dendritic cells - CCL19 + CCL21
What receptor does CCL19 and CCL21 bind to?
CCR7 expressed by T cells
What chemokine are B cells attracted by?
CXCL13 (BLC secreted by Follicular dendritic cells)
What receptor does CXCL13 bind to?
CXCR5 expressed by mature B cells
What other receptor does the mature B cells express at low levels?
CCR7 (that may account for their characteristic migration pattern)
Pop. of Pro-B cells:
80 x 10^6 /day
of which more than half will fail to make a productive heavy chain rearrangement
Pop. of Pre-B cells:
35 x 10^ 6 /day
of which about half will fail to make productive light chain gene rearrangement
some undergo Tolerance induction
Tolerance induction?
clonal deletion of B cells reactive to multivalent self-Ag
Pop. of Immature B cells:
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)
Pop. of Self-tolerant immature B cells:
become mature, long-lived, naive B cells
Pop. of mature, long-lived naive B cells
1-2 x 10^6 /day
(half-life of about 1-2 months - IgM low, IgD high)
What determines the fate of an immature B cell in the periphery?
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
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
What is the function of BAFF-R/BAFF?
It provides important signal for follicular 3B cell survival
BAFF-R KO mice:
they have mainly immature B cells and few long-lived peripheral B cells
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
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
What determines B-cell type commitment?
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
What are marginal zone B cells?
another unique subset of mature B cells that do not reside in the follicles but in the marginal zone of the spleen
Marginal zone B cells features:
- IgM high
- IgD low
- CD23 low/-
- NOT CD5+
- CD21 high
- have restricted BCR repertoire biased toward common bacterial Ag and self-Ags
B cell contributions:
-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
T-cell development:
Where does T-cell progenitor develop?
Bone marrow
Where does the precursor rearranges its T-cell precursor genes?
Thymus
Where does positive and negative slection of T-cell occur?
Thymus, and then the mature T cells migrate to the peripheral lymphoid organs
Where are the T-cells activated?
In peripheral lymphoid organs where they encounter foreign Ags, and then they migrate to the sites of infection
What receptor do the T-cells migrating to the thymus express?
Notch1 receptor, which also instructs progenitor cell to develop into a T-cell
What is the origin of the thymic epithelia?
third pharyngial pouch + third branchial cleft => thymic anlage (rudimentary thymus)
What cells colonize the thymic anlage?
T cell precursors + dendritic cells + macrophages
Describe the cell organization of the thymus.
- Lobules, which are each divided in...
- an outer cortex and an inner medulla
Where are the thymocytes localized?
in a network of epithelial cells known as the thymic stroma (cortical and medullary epithelial cells)
Waht cells are found in the cortex?
immature thymocytes
What cells are found in the medulla?
more mature thymocytes, dendritic cells and macrophages
What does the differential distribution reflect?
the different developmental events that occur within the 2 compartments
How is the rate of T cell production different from before to after puberty?
- greater before puberty
- after, thymus starts to shrink and produce less T cells
Is removal of thymus in adults fatal?
No, it is not accompanied by a loss of immunity
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
nude -
these mice have a defect affects cortical epithelium
T cell development stages:
- DN
- DP pre-TCR
- DP TCR
- SP
1. DN (double negative thymocytes)
- CD4 neg and CD8 neg
- will give rise to γδ T cells (minority) and αβ T cells (majority)
2. In αβ lineage, we then have DP pre-TCR (double positive)
- 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
3. SP (single positive thymocytes)
- 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
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
In what order does the beta chain locus rearrange itself ?
D -> J
V -> DJ
What happens when the beta chain locus has a productive rearrangement?
- 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
What happens when the alpha chain locus has a productive rearrangement?
- α chain pairs with β and thymocyte expresses an Ag-receptor at the surface
Differences between B and T cells:
- 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
What are the different stages of Double Negative? DN1
- DN1: Kit+, CD44+, CD25-; α and β chain genes in germline config
DN2:
- DN2: Kit+, CD44+, CD25+; Dβ -> Jβ starts
DN3:
- DN3: Kit-low, CD44-low, CD25+; Dβ -> Jβ continues; Vβ -> DJβ starts
DN4:
- DN4: Kit-, CD44-, CD25-;
- proliferation
- arrest of further β chain gene rearrangement (allelic exclusion)
DP:
- 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
SP:
expression of either CD4 OR CD8 on the TCR
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)
Major difference in rearrangement at the TCR α-chain:
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)
What are the consequences of continuous rearrangment at TCR α chain locus?
- increase the the production of useful T cells
- increases chance of generating T cells with 2 TCRs
What is the trajectory of a thymocyte in the thymus?
- DN1 (medulla)
- DN2 (cortex)
- DN3 (subcapsular region)
- DN4 immature DN (subcapsular region)
- immature DP (cortex)
- mature SP (cortico-medullary junction)
How does the T cell lineages diverge from their common precursor?
after certain gene rearrangement has already occured
How does rearrangement of γ, δ and β occur in DN?
simultaneously -> DN3 expresses both γδ TCR and a pre-TCR
How is one of the two TCR selected?
signalling through either its γδ TCR or αβ TCR
What happens if γδ TCR receives a signal?
cell switches off expression of beta chain and commits to the gamma-delta
What happens if the DN receives a signal through its pre-TCR?
- 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
When do γδ T cell first appear?
embryonic development, in discrete waves at first
1st wave:
populates epidermis (dendritic epidermal T cells - dETCs)
2nd wave:
populates reproductive epithelium
What is particular about the receptors expressed by the early waves of γδ T cells?
all the cells in each wave assemble the same Vγ and Vδ regions (no N-nucleotides additions)
What γ and δ chains are expressed in dETCs and the reproductive epithelium?
dETCs: Vγ5 (most proximal V gene)
reproductive epithelium: Vγ6 (2nd most proximal)
Both γ chains are expressed with the same δ-chain gene
How is the production of T cells after the embryonic stage?
continuous production -> αβ T cells predominate (95% of thymocytes)
Are γδ still produce after the embryonic stage?
Yes, they are found in lymphoid organs, have more diverse TCR repertoire (use several diff V gene segments and have N-nucleotide additions)