Flashcards in Lymphocyte Development And Antigen Receptor Gene Rearrangement Deck (93)
What events occur in generative lymphoid organs that result in maturation of T and B lymphocytes?
Commitment of progenitor cells to the B or T lymphoid lineage.
Proliferation of progenitors and immature lymphocytes.
Sequential and ordered rearrangement of Ag receptor genes and the expression of antigen receptor proteins.
Differentiation of B and T cells into functionally and phenotypically distinct subpopulations.
What do pluripotent stem cells give rise to?
Distinct B and T lineages.
What do hematopoietic stem cells give rise to?
Common lymphoid progenitors (CLPs)
What do common lymphoid progenitors (CLPs) give rise to?
B cells, T cells and NK cells.
Commitment to different lineages is driven by various transcription factors.
What can pro-B cells eventually differentiate into?
Follicular B cells
Marginal zone B cells
What do pro-T cells commit to?
Alpha beta T cells
Gamma delta T cells
What is the proliferation of the committed T and B cell progenitors stimulated by?
What is the function of proliferation?
It ensures that a large pool of progenitor cells is available for generation of a high diversity of mature lymphocytes.
What occurs when pre-Ag receptors are successfully rearranged?
It provides survival signals that select the cell.
What do stromal cells in the thymus produce?
This drives the proliferation fo human T cell progenitors.
What is the development of NK cells dependent on?
What does commitment to the B or T lineage depend on?
Sequential signaling from several cell surface receptors.
What is the function of signaling?
It activates transcription factors that contribute to the commitment via induction of gene expression and rearrangmements of the Ag receptor genes.
What occurs during the development of B cells?
The Ig heavy chain locus opens up and becomes accessible to the proteins that will mediate the Ig gene rearrangement and expression.
What occurs during the development of alpha-beta T cells?
The TCR beta gene locus opens up and becomes accessible for TCR gene rearragement and expression.
What is the function of Notch-1 and GATA-3 transcription factors?
They commit developing lymphocytes to the T cell lineage.
What are the noch family of proteins?
They are cell surface molecules that are proteolytically cleaved when they interact with specific ligans on neighboring cells.
The cleaved intracellular portion of notch protein migrates to the nucleus and modulates the expression of specific target genes.
What is the function of EBF, E2A and Pax5?
They are transcription factors that induce the expression of genes required for B cell development.
EBF, E2A and Pax-5 are transcription factors that induce the expression of genes required for B cell development. What genes do they encode?
Rag-1 and Rag-2 that regulate BCR rearragement
The surrogate light chains (pre-B cell receptor)
The Ig alpha and Ig beta signalign proteins of the B cell receptor complex.
What is the result of DNA methylation on cytosine residues?
It generally silences genes.
What is the function of modifications of histone tails of nucleosomes?
They render genes either in either the active or inactive state.
Is euchromatin tightly or loosely packed?
This makes genes available to be transcribed.
What occurs as a result of modifications of the histone tails of nucleosomes?
They either render genes as active or inactive.
Active remodeling of chromatin by proteins forming the remodeling complexes can either enhance or suppress gene expression.
What are microRNAs?
A class of small noncoding RNAs that control gene expression at the post-transcriptional level by impairing translation or by promoting degradation of the target mRNA
Individuals codominantly interit maternal and paternal sets of alleles of L and H chains. However, only one of the VlCl and VhCh alleles is expressed on a single B cell. What is this restriction termed?
It also governs the expression of TCR.
What do stem cells contain?
Germline Ig and TCR.
What are the variable regions of the chains in the T and B cells determined by?
Rearrangement of DNA.
DNA chromosomal rearrangmement is the major mechanism of epitope-specific diversity of BCR and TCR. What are the three mechanisms?
The process includes deletion of DNA/RNA nucleotides and reannealing gene segments.
What are the four separate gene segments in chromosome 14?
V - variable
D - diversity
J - joining
C - constant
In a single B cell all copies but one are randomly deleted giving a unique combination of V-D-J.
Each B cell generates its own V-D-J sequence and thus all B cells are different.
What is the function of Rag 1 and 2?
They encode enzymes performing recombination of BCR and TCR during the process of VDJ recombination.
What is the cellular expression of Rag 1 and 2 restricted to?
B and T lymphocytes during their developmental stages.
In mature B cells, each DNA segment is present as a ____.
How is BCR diversity achieved?
First, D and J are chosen and DNA inbetween them is deleted.
The V segment is chosen nd DNA between V and DJ is deleted.
J is chosen and DNA between VDJ and C is deleted.
After D, J, and V segment are chosen, what occurs in BCR diversity?
There will be a test (transcription + translation) for a selection of productive rearrangement.
When productive rearrangement is confirmed, the competition is over and the recombination of other segments is stopped.
If the Vh rearragement is productive, then:
B cell proliferates for awhile and "Takes care" of the Vl.
The recombination rules are the same for the Vl chain.
After the Vh rearrangement occurs, there will be a second test for the selection of productive rearrangment, this time for the Vl sequence. What is the final result?
Each B cell produces only one kind of Vh and VL.
Why can B cells produced recognize any Ag possible?
Because the number of combinations possible is very big.
In each B cell, what happens to the rearranged gene?
It is transcribed, spliced and translated into a H-chain portion.
Is the VDJ recombination enough to produce a hugh variety of TCRs and BCRs which would recognize all antigens possible?
But the inaccuracies of joining achieved by junctional diversity further increases the diversity of TCRs and BCRs.
Where is junctional diversity generated?
At the points between the joining genes.
What does junctional diversity result from?
The loss of nucleotides through the action of exonucleases and from the additional of N and P nucleotides.
What does an asymmetric opening of hairpin loops generate?
It is the self-complementarity of P nucleotides that leads to their palindromic appearance and to their name.
What does the opening of hairpin loops produce?
Short, self-complementary single stranded extenses that can be incorporated into junctions, or can be removed via an exonuclease activity.
What occurs during lymphocyte development?
Cells go through numerous checkpoints at which the developing cells are tested and continue to mature only if a preceding step in the process has been successfully completed.
When does checkpoint 1 in the selection process occur?
It occurs after the production of the first polypeptide chain of the two chain Ag receptor in completed.
When does the second checkpoint of the selection process occur?
It follows the production of the second polypeptide chain of the Ag receptor is completed.
What is the purpose of checkpoints in the selection process?
Checkpoints ensure that only lymphocytes that have successfully completed Ag receptor gene rearrangement processes are selected to mature.
What is a purpose of the selection process?
It eliminates potentially harmsful self-reactive lymphocytes.
What is the function of the pre-Ag and Ag receptors?
They deliver survival signals for their proliferation and continued maturation.
What are pre-Ag receptors called in B cells and T cells?
They are pre-BRCs in B cells and pre-TCRs in T cells.
The pre-Ag receptors contain only one polypeptide chain present in a mature Ag receptor.
The pre-BCRs contain the Ig mew heavy chain
The pre-TCRs contain the TCR beta chain.
What is the first Ag receptor gene to be completely rearranged in B cells?
The Ig heavy chain.
Developing B cells that successfully rearrange their Ig heavy chain genes express the mew heavy chain protein and assemble the pre-TCR.
What occurs if cells make out of frame rearragnements?
The pre-Ag receptors are not expressed, the cells do not receive survival signals and under apoptosis.
What do assembled pre-BCRs and pre-TCRs provide signals for?
Survival, proliferation and further development of early B and T lineage cells.
B and T lymphocytes with functional pre-Ag receptors proceed to expressed genes encoding the __ of the BCR or TCR.
If these cells make productive rearrangements of the 2nd chain, they express the complete Ag receptor while they are still immature.
Lymphocytes that express useful Ag receptors are preserved by a process called ____.
In the T cell lineage, what does positive selection ensure?
It ensures the maturation of CD8 or CD4 T cells whose receptors recognize appropriate self MHC molecules.
T cells positively selected by self-MHC molecules in the thymus are able to ...
Recognize foreign Ag displayed by the same self MHC moleculs on APCs in peripheral tissues.
How are potentially harmful T cells that strongly recognize self Ags eliminated?
What occurs to potentially harmful B cells that strongly recognize self Ag?
They are induced to rearrange their second chain of Ag receptors again.
What occurs to B and T lymphocytes with functional pre-Ag receptors?
They proceed to express genes encoding the second chain of the BCR or TCR.
If these cells make productive rearrangements of the second chain, they express the complete Ag receptor while they are still immature.
Lymphocytes that express useful Ag receptors are preserved by what process?
What does positive selection of T cells ensure?
The maturation of CD8 or CD4 T cells whose receptors do not recognize MHC molecules.
What are T cells positively selected by self MHC molecules able to recognize?
Foreign Ag displayed by the same self MHC molecules on APCs in peripheral tissues.
What is negative selection of immature lymphocytes important for?
It is an important mechanism for maintaining the central tolerance to many self Ags.
When does negative selection occur?
Shortly after Ag receptors are first expresed on developing B and T cells.
What is the function of negative selection?
It eliminates harmful T cells and alters harmful B cells whose Ag receptors bind strongly to self Ags presentin the thymus or bone marrow.
How are developing harmful T cells with a high affinity for self Ags eliminated?
By apopstosis/clonal deletion.
Developing harmful B cells with a high affinity for self Ags undergo the second attempt in Ig gene rearrangement, a process called ....
If editing fails, self-reactive B cells die, also called ..
What do B-1 cells develop from?
Fetal liver-derived HSCs.
Why do B-1 cells express limited BCR diversity?
Because TdT is not expressed in the fetal liver.
Where are large numbers of B-1 cells found?
As self-renewing population in the peritoneum and mucosal sites.
What do B-1 cells spontaneously secrete?
IgM Abs that often react with microbial polysaccharides and lipids, as well as oxidized lipids.
Why IgM Abs sometimes called natural antibodies?
They are present in individuals without overt stimulation.
B-1 B cells contribute most of the serum IgM during the early phases of infection.
What do B-2 cells develop from?
HSCs in the bone marrow.
Following rearrangement of their BCR chain genes and removal of autoreactive cells vial cell tolerance, where do immature B-2 B cells relocate to?
What do immature B-2 B cells differentiate into?
MZ B cells or mature follicular B-2 Cells.
Where do marginal zoen (MZ) B cells localize to?
The splenic marginal zone. They respond to blood-borned antigens here.
Follicular B cells require constant replenishment from where?
The bone marrow.
Follicular B-2 cells respond to protein Ags in a t ell dependent manner, and progressively undergo immunoglobulin isotype switching and ____
What type of B cells, upon T cell dependent activation, develop into long lived plasma cells or memory B cells?
Mature follicular B-2 cells.
The MZ B cells are predominantly ____
Responses of MZ B cells are independent of T cell help.
Where are marginal zone B cells located?
Primarily in the vicinity of the marginal sinus in the spleen.
Similar to B-1 cells, MZ B cells have BCRs of limited diversity which respond to polysaccharide Ags and to generate natural Abs.
Where ccan MZ B cells be found?
Spleen and lymph. Nodes.
What do marginal zone B cells respond very rapidly to?
Blood-borne microbes and differentiate into short-lived secreting plasma cells.
Although they generally mediate T-cell independent humoral immune responses to circulating pathogens, marginal zone B cells also appear capable of ...
Mediating some T cell-dependent immune responses.
Recombination of TCR gamma and delta loci proceeds in a fashion similar to that of TCR beta and alpha, although the ...
Order of rearrangement appears to be less rigid.
True or false: the rearrangement of TCR beta, gamma or delta loci is initiated simultaneously.
If a cell first succeeds in produtively rearranging its TCR gamma or delta loci before it makes a productive TCR beta rearrangement, it is selected into the ____
Gamma delta T cell lineage.
This happens in about 10% of developing T cells become gamma detla T cells.
About 90% of developing T cells become alpha beta T cells.
Why is there a limited diversity of expressed gamma detla TCRs?
Because only a few of the available V, D and J segements are used in mature gamma delta cells for unknown reasons.