Lecture 8: Lymphocyte Development and Antigen Receptor Gene Rearrangement

Question 1

where does sequential and ordered rearrangement of Ag receptor genes and the expression of antigen receptor proteins occur

Answer 1

Generative Lymphoid organs

Question 2

What are the transcription factors that cause a common lymphoid progenitor cell to differentiate into Pro-B cells

Answer 2

EBF, E2A, and Pax5

Question 3

What are the transcription factors that cause a common lymphoid progenitor cell to differentiate into T cell precursor cells

Answer 3

Notch 1 and GATA3

Question 4

Pro-B cells differentiate into

Answer 4

• Follicular (FO) B cells
• Marginal zone (MZ) B cells
• B-1 cells

Question 5

In the thymus, stromal cells produce ____ that drives the proliferation of human T cell progenitors

Answer 5

IL-7

Question 6

The development of NK cells is dependent on ____

Answer 6

IL-15

Question 7

In developing B cells the ______ locus opens up and becomes accessible to the proteins that will mediate Ig gene rearrangement and expression

Answer 7

Ig heavy chain

Question 8

In developing alpha/beta T cells the ______ opens up and becomes accessible for TCR gene rearrangement and expression

Answer 8

TCR beta gene locus

Question 9

EBF, E2A, and Pax-5 transcription factors that induce the

Answer 9

• 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

Question 10

DNA methylation of certain cytosine residues generally ____ genes

Answer 10

silences

Question 11

_____ 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)

Answer 11

microRNAs (miRs)

Question 12

What is allelic exlusion

Answer 12

• Individuals codominantly inherit maternal and paternal sets of alleles for L and H chains
• however, only one of the V_LC_L and V_HC_H alleles (either maternal or parental) is expressed in a single B cell
• This is also the case in TCR

Question 13

Stem cell (a precursor of both T and B cells) contains germline __ and ___

Answer 13

Ig and TCR

Question 14

what are the 3 mechanisms of rearrangement of DNA to form variable regions of chains in T and B cells

Answer 14

• Somatic recombination
• mRNA splicing
• Juncitonal diversity

Question 15

Question 16

The H-chain of Ig polypeptide is on chromosome

Answer 16

14

Question 17

The k-chain of Ig polypeptide is on chromosome

Answer 17

2

Question 18

The gamma chain of Ig polypeptide is on chromosome

Answer 18

22

Question 19

The heavy chain of B cell has __ separate gene sements in chromosome 14

Answer 19

4 (V, D, J, C)

Question 20

____ and ___ encode ezymes performing recombination of BCR and TCR during the process of VDJ recombination

Answer 20

RAG1 and RAG2 (Recombination-activating genes 1 and 2)

Question 21

The cellular expression of RAG1 and RAG2 is restricted to B and T lymphocytes during

Answer 21

their developmental stages (makes sense because you don’t want VDJ recombination later in life-cycle)

Question 22

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 ___

Answer 22

• TCR (3x10⁶)
• BCR (10⁶)
• but the inaccuracies of joining achieved by junctional diversity further increases the diversity of TCRs (10¹⁶)and BCRs (10¹¹)

Question 23

Question 24

Question 25

BCR recombination occurs in what order

Answer 25

* 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

Question 26

The largest contribution to the diversity of antigen receptors is made by the

Answer 26

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)

Question 27

When are the checkpoints in lymphocyte development

Answer 27

* 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

Question 28

Pre-Ag receptors contain only one polypeptide chain present in the mature Ag receptor: name them

Answer 28

* 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

Question 29

Most B cells that develop from fetal liver-derived stem cells differentiate into the ___ lineage

Answer 29

B-1

Question 30

B lymphocytes that arise from bone marrow precursors after birth give rise to the -\_\_\_ lineage

Answer 30

* 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

Question 31

Why do B-1 cells express a limited BCR diversity

Answer 31

* 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

Question 32

The large numbers of B-1 cells are found as self-renewing population in the ___ and _____ sites

Answer 32

peritoneum and mucosal sites

Question 33

B-1 cells spontaneously secrete ___ Abs that often react with microbial polysaccharides and lipids as well as oxidized lipids

Answer 33

* 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

Question 34

Marginal zone (MZ) B cells localize to the _____ and respond to \_\_\_\_

Answer 34

* splenic marginal zone * and respond to blood-borne Ags

Question 35

following rearrangement of their BCR chain genes and removal of autoreactive cells via central tolerance, immature B-2 cells relocate to the

Answer 35

spleen

Question 36

Follicular B cells respond to ____ Ags in a ______ manner, and progressively undergo immunoglobulin ________ and \_\_\_\_\_

Answer 36

Follicular B cells respond to protein Ags in a T cell-dependent manner, and progressively undergo immunoglobulin isotype switching and affinity maturation

Question 37

Only mature ______ upon T-cell dependent activation develop into long-lived plasma cells or memory B cells

Answer 37

Follicular B-2 cells

Question 38

similar to B-1 cells, MZ B cells

Answer 38

have BCRs fo limited diversity which respond to polysaccaride Ags and generate natural Abs

Question 39

MZ B cells respond very rapidly to ____ and differentiate into

Answer 39

Marginal zone B cells respond very rapidly to blood-born microbes and differentiate into short-lived IgM-secreting plasma cells

Question 40

Explain gamma/delta T cells are developed instead of alpha/beta T cells from the Progenitor-T cells

Answer 40

* 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

Question 41

Why is there a limited diversity of gamma/delta TCRs

Answer 41

becuase only a few of the available V, D, and J segments are used in mature Gamma/delta T cells