Jitt # 3 Lymphocyte Development and Antigen Receptor Gene Rearrangement ( 171 - 176 & 184 - 190)

Question 1

What are the five steps in Lymphocyte development?

Answer 1

1) Commitment of progenitor cells
2) Proliferation
3) Gene rearrangement
4) Selection events
5) Differentiation of B/T cells

Question 2

What is the progenitor of all lineages of blood cells and lymphocytes? Where are they located?

Answer 2

HSCs Hematopoietic stem cells are the progenitors of all blood cells, including lymphocytes. They are located in the fetal liver and bone marrow.

Question 3

What two transcription factors commit developing lymphocytes to the T cell lineage?

Answer 3

Notch-1 and GATA-3; Notch-1 is cleaved and intracellular portions migrate to the nucleus which, along with GATA-3 induce genes that cause development of T cells.

Question 4

What are the three transcription factors that help commit developing lymphocytes to the B cell lineage?

Answer 4

EBF, E2A, and Pax-5 induce the expression of genes (Rag-1, Rag-2, surrogate light chains, Ig alpha and Ig beta) which are all involved in B-cell development.

Question 5

What is the role of IL-7 in lymphocyte maturation?

Answer 5

IL-7, in humans, is responsible for the proliferation of B/T cell progenitors. IL-7 is produced by stromal cells of the bone marrow and epithelial cells of the thymus.

Question 6

X-SCID

Answer 6

X-linked severe combined immunodeficiency disease; caused by mutations in the gamma chain, which is a protein shared by receptors for several chemokines (IL-2, IL-7 and IL-15); characterized by a block in T cell and NK cell development.

Question 7

What is the role of IL-15 in development of ILCs?

Answer 7

Recall that ILCs are bone marrow derived cells with lymphoid morphology and function to that of T cells, but lack T cell antigen receptors. IL-15 is important for the proliferation and maturation of NK cells.

Question 8

Where are functional receptor genes for B/T cells developed?

Answer 8

Bone marrow for B cells, Thymus for T cells by gene rearrangement.

Question 9

What are checkpoints? Why are they important?

Answer 9

Checkpoints are steps in lymphocyte development that check for functionality (lymphocyte has complete receptor), non reactivity to self antigens, and to move lymphocytes for maturity

Question 10

pre-BCRs/pre-TCRs

Answer 10

Pre antigen receptors are expressed by early lymphocytes. Ig u and TCR beta respectively. This is the first checkpoint. After the first checkpoint, rearrangement occurs again, of the light chains to generate a complete BCR or TCR

Question 11

Positive selection

Answer 11

The process by which lymphocytes that are non-pathogenic to self and that have useful receptors are chosen to continue on with maturation.

Question 12

Positive selection for T Cells

Answer 12

In the T-Cell lineage, all T cells that recognize self MHC molecules continue on to maturation. (also express coreceptor CD8 or CD4)

Question 13

Negative selection

Answer 13

the process that eliminates or alters developing lymphocytes whose antigen receptors bind strongly to self antigens present in the generative lymphoid organs.

Question 14

Receptor editing

Answer 14

The process by which self-reactive immature B cells are induced to make further Ig gene rearrangements, thus evading self-reactivity. RAG reactivated and new light chains are generated. If this doesn’t work, then lambda chains are used

Question 15

Clonal deletion

Answer 15

The process by which developing T/B cells with high affinity for self are eliminated by apoptosis

Question 16

VDJ recombination

Answer 16

V- Variable region; D - Diversity region; J - Joining region. Three segments on chromosomes that are responsible for the generation of diverse receptors on lymphocytes

Question 17

D segments are not found in what type of Ig chain?

Answer 17

1) Ig light chains (Both produce recombination with only V/J segments) 2) Ig heavy chains have V regions that are coded by VD&J (also TCR ß)

Question 18

What are the sources of hyper-variability in receptors?

Answer 18

1) VDJ recombination (Each letter having different gene selection within itself) 2) variability in the junctional sequences between the V and D segments and the D and J segments 3) Variability in the V and J region and the J segment itself

Question 19

CDR3

Answer 19

Complementarity-determining region 3 variability in the junctional sequences between the V and D region and the D and the J region

Question 20

How are the developmental stages of B lymphocytes distinguished from each other?

Answer 20

By distinct cell surface markers and a specific pattern of Ig gene expression.

Question 21

Pro- B cell

Answer 21

The earliest bone marrow cell committed to B-cell development. Does not express Ig, but is distinguishable by the presence of CD19 and CD10. Rag-1 and Rag-2 are first generated. D/J recombine first, then V joins. Rearrangement occurs at the Ig H locus.

Question 22

Pre-B cells

Answer 22

Developing B lineage cells that express the Ig u protein but have yet to rearrange their light chain loci.

Question 23

pre-BCR

Answer 23

pre B cell receptor. Made up of u heavy chains associated with lambda 5 and V pre-B proteins (surrogate light chains). (Ig alpha, Ig beta are in mature lymphocytes)

Question 24

BTK

Answer 24

Burton’s Tyrosine Kinase. Kinase activated downstream of the pre-BCR receptor. BTK is responsible for the transmission of signals that mediate survival, proliferation, and maturation

Question 25

What is the first checkpoint in B Cell maturation?

Answer 25

the expression of pre-BCR

Question 26

XLA

Answer 26

X-linked agammaglobulinemia. mutation in the BTK gene. Causes failure of B Cell maturation.

Question 27

What are the two ways that pre-BCR regulates further rearrangement of Ig genes?

Answer 27

1) One heavy chain is rearranged, while the other is left in the germ-line configuration, due to signals received by pre-BCR. If neither alleles produce Ig heavy chains, then they cannot generate a pre-BCR-dependent survival signal signal (undergoes apoptosis) 2) Stimulation of k light chain rearrangement/ inactivation of surrogate light chain gene expression.

Question 28

Allelic exclusion

Answer 28

The process by which only one allele of a heavy chain is expressed, while another is left constant. This is what causes a B cell to have only one RECEPTOR!!!!!

Question 29

Immature B Cells

Answer 29

IgM expressing B cell. IgM is produced when k light chains interact with u chains to produce a complete IgM protein.

Question 30

What happens if the k chain is not rearranged correctly or is self-reactive?

Answer 30

the lambda chain becomes rearranged and production of IgM occurs. If both lambda and k chains are non-functional, the cell stops receiving survival signals BCR and undergoes apoptosis.

Question 31

Mature B Cell

Answer 31

Co-express IgD and IgM. Production of IgD is associated with functional competence. Are now reactive to antigens.