lymphocyte development and antigen receptor gene rearrangement Flashcards
B/T cell maturation
commitment:
TFs responsible for B cell commitment:
TFs responsible for T cell commitment:
activation of TFs shifting to pro-B/T cells
EBF, E2A, Pax-5
Notch-1 and GATA-3
B/T cell maturation
proliferation:
simulated by IL-7 in the bone marrow or thymus
B/T cell maturation:
selection:
survival of functional receptors that are not self-reactive
B/T cell maturation:
differentiation:
diversion into functional subgroups
hematopoietic stem cells → _____ → ____ , ____ , and ____
hematopoietic stem cells → common lymphoid progenitor → B cells (in bone marrow), T cells (in thymus), and NK cells (in bone marrow)
pro-B cells can eventually differentiate into:
1.
2.
3.
- FO B cells (follicular)
- MZ B cells (marginal zone)
- B-1 cells
Pro-T cells may commit to either:
1.
2.
- alpha-beta T cells
- gamma-delta T cells
commitment to different lineages is driven by
various TFs
proliferation of committed T and B cell progenitors is stimulated by
cytokines
_____ drives the proliferation of human T cell progenitors in the thymus and promotes B cell development in the bone marrow
IL-7 (produced by stromal cells)
the development of NK cells occurs in the ______ and it depends on ______
bone marrow
IL-15
early commitment to the B lineage:
first the Ig _____ chain locus opens up and becomes accessible to the proteins that will mediate Ig gene rearrangement and expression
heavy
early commitment to the T lineage: (alpha-beta T cells)
first the TCR ____ gene locus opens up and becomes accessible for TCR gene rearrangement and expression
beta
DNA methylation on ______ residues generall ______ genes
cytosine
silences
the modifications os histone tails of nucleosomes by post-translational _____ , ______ , or _____ render genes either active or inactive
acetylation, methylation, or ubiquitination
miRNAs are a class of small noncoding RNAs that control gene expression at the ______ level by impairing translation or by promoting degradation of the mRNA. miRNAs can also accumulate in the nuclei and regualte gene expression at the trascriptional level
post-transcriptional
individuals _____ inherit maternal and paternal sets of alleles for L and H chains of Ig molecules
however;
only one of the light chain and heavy chain alleles (either maternal or paternal) is _______ in a single B cell
this is called:
codominantly
expressed
allelic exclusion (similar for TCR)
the ______ regions of the chains in T and B cells are determined by rearrangement of the DNA
variable
DNA chromosomal rearrangement is the major mechanism of ____ ____ of BCR and TCR
epitope-specific diversity
3 mechanisms for BCR and TCR diversity:
1.
2.
3.
- somatic recombination - V (D) J combination
- junctional diversity (non-homologous end joining)
- mRNA splicing
BCR/TCR construction:
- BCR _____ chain and TCR _____ chain made first
- checks to make sure the first chain was made; _____ chain used
- BCR _____ chain and TCR _____ chain made second
- check to make sure that functional _____ chain was made
- heavy beta
- surrogate
- light alpha
- second
BCR/TCR genes:
- located on chromosome _____
- B cell heavy chain and T cell beta chains, consist of what segments:
- B cell light chain and T cell alpha chain, consist of what segments:
- each segment has multiple copies but all copies except one are _____ giving a unique combination
- 14
- (V)ariable, (D)iversity, (J)oining, and (C)onstant
- (V)ariable, (J)oining, and (C)onstant
- randomly deleted
____ and ____ encode enzymes that perform recombination of BCR and TCR during the process of VDJ recombination
RAG1 and RAG2
the cellular expression of RAG1 and RAG2 is restricted to B and T lymphocytes only during their ____ stages
developmental
How is BCR diversity achieved:
- first ____ are chosen and DNA in between them is deleted
- second ____ segment is chosen and DNA between V and DJ is deleted
- third a _____ segment is chosen and DNA between VDJ and C is deleted
- there will be a test for slection of productive rearrangement with help of a:
- when productive rearrangement is confirmed, the competition between ____ and ____ heavy chain genes is over and the recombination of other segments is stopped
- D and J segments
- V segment
- C segment
- surrogate light chain
- maternal and paternal
somatic recombination is the process of talking all the copies of the different sements and
choosing only one of each
(changes are made to the DNA itself)
Rearrangement occurs in a specific order:
BCR heavy chain and TCR beta chain:
- ___ and ___ segments are chosen first, DNA between them is deleted
- ___ segment is chosen, DNA between it and DJ segment is deleted
BCR light chain and TCR alpha chain:
- ___ and ___ segments are chosen, DNA between them is deleted
BCR heavy chain and TCR beta chain:
- D and J segments
- V segment
BCR light chain and TCR alpha chain:
- V and J
mRNA splicing:
- RNA transcript is made from _____ DNA
- alternative splicing of the ___ segments in BCR result in ____ and ____ variants of BCR
- this does not apply to ___ , ___ , or ___
- recombined
- C segments IgM and IgD
- IgG, IgA, or IgE
junctional diversity:
- during rearragement, ___ ___ ___ are made in the DNA flanking chosen segment
- DNA strands are ligated via ___ with cosen segments now adjacent to each other
- new, novel ___ sequences are created
- double stranded breaks
- NHEJ
- DNA
what is responsible for most of the diversity in BCR/TCR
junctional diversity
___ creates asymmetric opening in hair pin loop of DNA
RAG
gap between two ends (of cut DNA by RAG) is filled with random, untemplated sequence of nucleotides by ___
TdT
selection:
- tests to ensure that ____ was actually produced (no out of frame rearrangements)
- final receptors don’t recognize ____
- final ___ recognize MHC I/II
- if any of these fail, cells
- chain
- self-Ag
- TCR
do not reeive required survial signals and will die
first selection:
- BCR ___ chain and TCR ___ chain is tested
- ___ light chain and alpha chain are ued temporarily
- BCR heavy chain only uses ___ constant region (__) , delta not seen at this time
- heavy beta
- surrogate
- mu (IgM)
second selection:
- BCR ___ chain and TCR ___ chain tested
- BCR heavy chain can use both ___ and ___ constant regions
- if functional BCR/TCR is made, cell undergoes ____ selection
- light alpha
- mu and delta
- positive/negative selection
positive selection:
- completed TCR/BCR does not:
- TCRs must recognize ____
- these cells live on to become:
- self-Ag
- MHC
- immature B/T cells
negative selection:
- completed TCR/BCR recognizes _____
- self-reactive TCRs undergo:
- self-reactive BCR undergoes:
- TCRs that don’t recognize ____ are deleted
- negative selection is responsbile for generating ____ ____
- self-Ag
- clonal deletion (by apoptosis)
- BCR editing
- MHCs
- central tolerance
BCR editing:
- BCRs are initially made using the ___ chain
- if the B cell using the kappa chain is negatively selected, instead of undergoing clonal deletion, it tries again using the ___ chain
- after the lambda chain is recombined, it goes through the ____ round of selection again
- if ti fails this time, the B cell undergoes ___ ___ just like the T cell did
- kappa
- lambda
- second
- clonal deletion
the VDJ rearrangement segment facilitates the synthesis of a ___ or ___ heavy chain controlled by ___ ___ ___ . this then associates with a light chain, thereby forming an ___ or ___ molecule, which is displayed on the cell-surface of a naive B cell
mu or delta
alternative mRNA splicing
IgM or IgD
___ introduces a break in the DNA that is responsible for class-switch recombination to other Ig classes (other than IgM/IgD)
AID (activation-induced cytidine deaminase)
AID is only expressed in
activated B cells
RAG cleaves ___ and adds ___ nucleotides
hairpin loops
P
TdT adds ___ nulceotides
N
B-1 cells:
- are made it:
- no ___ and no ___ diversity
- reside in:
- only secrete ___
- ___ population
- fetal liver
- no TdT and no junction diversity
- peripheral tissues
- IgM
- self-renewing population
B-2 cells:
- are made in:
- do have ___ and ___ diversity
- reside in:
- can produces all ___
- bone marrow
- have TdT and junctional diversity
- circuate in blood or reside in lymphoid organs
- isotypes
B-2 cell subsets:
1.
2.
- FO B cells (follicular B cells)
- MZ B cells (marginal zone B cells)
FO B cells characteristics:
1.
2.
3.
4.
- circulating population
- greater diversity, undergo affinity maturation
- mostly T cell dependent/isotype switched
- differentiate into long-lived plasma cells OR memory B cells
MZ B cell characteristics:
1.
2.
3.
4.
- located in marginal zone of spleen or LNs
- less diversity
- mostly T cell-independent (IgM)
- differentiate into short lived plasma cells
FO B2 cells respond to ____ Ags
protein
FO B2 cells, upon T cell dependent activation, develop into
long lived plasma cells or memory B cells
similar to B1 cells, MZ B cells have ___ diversity which resopnse to ___ Ags and generate ___ Abs
limited
polysaccharide
natural
while the TCR beta chain is rearranging, the ___ and ___ are also rearranging
gamma chain and delta chain
roughly ___ % of developing T cells become gamma/delta T cells
10
gamma/delta T cells have very ___ diversity
limited
