Lecture 8: Lymphocyte Development and Antigen Receptor Gene Rearrangement Flashcards
where does sequential and ordered rearrangement of Ag receptor genes and the expression of antigen receptor proteins occur
Generative Lymphoid organs
What are the transcription factors that cause a common lymphoid progenitor cell to differentiate into Pro-B cells
EBF, E2A, and Pax5
What are the transcription factors that cause a common lymphoid progenitor cell to differentiate into T cell precursor cells
Notch 1 and GATA3
Pro-B cells differentiate into
- Follicular (FO) B cells
- Marginal zone (MZ) B cells
- B-1 cells
In the thymus, stromal cells produce ____ that drives the proliferation of human T cell progenitors
IL-7
The development of NK cells is dependent on ____
IL-15
In developing B cells the ______ locus opens up and becomes accessible to the proteins that will mediate Ig gene rearrangement and expression
Ig heavy chain
In developing alpha/beta T cells the ______ opens up and becomes accessible for TCR gene rearrangement and expression
TCR beta gene locus
EBF, E2A, and Pax-5 transcription factors that induce the
- expression of genes required for B cell development
- these include genes encoding:
- Rag-1 and Rag-2
- proteins regulating the BCR rearrangment
- The surrogate light chains (pre-B cell receptor)
- The Igalpha and Igbeta signaling proteins of the B cell receptor complex
- the Igalpha and Igbeta signaling proteins of the B cell receptor complex
- Rag-1 and Rag-2
DNA methylation of certain cytosine residues generally ____ genes
silences
_____ are a class of small noncoding RNAs (about 22 nucleotides) that control gene expression at the post-transcriptional level by impairing translation or by promoting degradation of the target messenger RNA (mRNA)
microRNAs (miRs)
What is allelic exlusion
- Individuals codominantly inherit maternal and paternal sets of alleles for L and H chains
- however, only one of the VLCL and VHCH alleles (either maternal or parental) is expressed in a single B cell
- This is also the case in TCR
Stem cell (a precursor of both T and B cells) contains germline __ and ___
Ig and TCR
what are the 3 mechanisms of rearrangement of DNA to form variable regions of chains in T and B cells
- Somatic recombination
- mRNA splicing
- Juncitonal diversity
The H-chain of Ig polypeptide is on chromosome
14
The k-chain of Ig polypeptide is on chromosome
2
The gamma chain of Ig polypeptide is on chromosome
22
The heavy chain of B cell has __ separate gene sements in chromosome 14
4 (V, D, J, C)
____ and ___ encode ezymes performing recombination of BCR and TCR during the process of VDJ recombination
RAG1 and RAG2 (Recombination-activating genes 1 and 2)
The cellular expression of RAG1 and RAG2 is restricted to B and T lymphocytes during
their developmental stages (makes sense because you don’t want VDJ recombination later in life-cycle)
The proceess of V(D)J recombination generates a repertoire of different TCR _____ and BCR ____ molecules for recognition of various microbial antigens
but the inaccuracies of joining achieved by junctional diversity further increases the diversity of TCRs ___ and BCRs ___
- TCR (3x106)
- BCR (106)
- but the inaccuracies of joining achieved by junctional diversity further increases the diversity of TCRs (1016)and BCRs (1011)
BCR recombination occurs in what order
- First, D and J are chosen and DNA between them is deleted
- Seond, V segment is chosen and DNA between V and DJ is deleted
- Lastly, J is chosen and DNA between VDJ and C is deleted
The largest contribution to the diversity of antigen receptors is made by the
removal or addition of nucleotides at the junctions of the V and D, D and J, or V and J segments at the time these segments are joined (junctional diversity)
When are the checkpoints in lymphocyte development
- Checkpoint #1: is after the production of the first polypeptide chain of the two-chain Ag receptor is completed
- Checkpoint #2: follows the production of the second polypeptide chain of the Ag receptor is completed
Pre-Ag receptors contain only one polypeptide chain present in the mature Ag receptor: name them
- Pre-BCRs: contain Ig u heavy chain
- Pre-TCRs: contian the TCR beta chain
- (this makes sense because they are the first to be rearranged in there respective lineages)
- note that it is the assembled pre-BCRs and pre-TCRs that provide signals for survival, proliferation, and further development of early B and T lineage cells
Most B cells that develop from fetal liver-derived stem cells differentiate into the ___ lineage
B-1
B lymphocytes that arise from bone marrow precursors after birth give rise to the -___ lineage
- B-2
- The affinity fo the BCRs for self Ags may contribute to differentiation of B-2 cells into:
- Follicular B-2 cells: which are recirculating lymphocytes
- Marginal zone B-2 cells: which are abundant in the spleen and also found in LNs
Why do B-1 cells express a limited BCR diversity
- because Tdt is not expressed in the fetal liver
- Tdt (Terminal deoxynucleotidyl transferase) is an enzyme that adds 20 non-template-encoded nucleotides called N nucleotides
The large numbers of B-1 cells are found as self-renewing population in the ___ and _____ sites
peritoneum and mucosal sites
B-1 cells spontaneously secrete ___ Abs that often react with microbial polysaccharides and lipids as well as oxidized lipids
- IgM
- Thes Abs are sometimes called natural antibodies because they are present in individuals without overt immunization
- B-1 cells contribute most of the serum IgM during the early phases of infection
Marginal zone (MZ) B cells localize to the _____ and respond to ____
- splenic marginal zone
- and respond to blood-borne Ags
following rearrangement of their BCR chain genes and removal of autoreactive cells via central tolerance, immature B-2 cells relocate to the
spleen
Follicular B cells respond to ____ Ags in a ______ manner, and progressively undergo immunoglobulin ________ and _____
Follicular B cells respond to protein Ags in a T cell-dependent manner, and progressively undergo immunoglobulin isotype switching and affinity maturation
Only mature ______ upon T-cell dependent activation develop into long-lived plasma cells or memory B cells
Follicular B-2 cells
similar to B-1 cells, MZ B cells
have BCRs fo limited diversity which respond to polysaccaride Ags and generate natural Abs
MZ B cells respond very rapidly to ____ and differentiate into
Marginal zone B cells respond very rapidly to blood-born microbes and differentiate into short-lived IgM-secreting plasma cells
Explain gamma/delta T cells are developed instead of alpha/beta T cells from the Progenitor-T cells
- The Rearrangement of TCR beta, gamma (or delta) loci is initiated simultaneously
- if a cell first succeeds in productively rearranging its TCR gamma or TCR delta loci before it makes a producitive TCR beta rearrangement, it is selected into the gamma/delta T cell lineage
Why is there a limited diversity of gamma/delta TCRs
becuase only a few of the available V, D, and J segments are used in mature Gamma/delta T cells
