Jitt # 3 Lymphocyte Development and Antigen Receptor Gene Rearrangement ( 171 - 176 & 184 - 190) Flashcards
(31 cards)
What are the five steps in Lymphocyte development?
1) Commitment of progenitor cells
2) Proliferation
3) Gene rearrangement
4) Selection events
5) Differentiation of B/T cells
What is the progenitor of all lineages of blood cells and lymphocytes? Where are they located?
HSCs Hematopoietic stem cells are the progenitors of all blood cells, including lymphocytes. They are located in the fetal liver and bone marrow.
What two transcription factors commit developing lymphocytes to the T cell lineage?
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.
What are the three transcription factors that help commit developing lymphocytes to the B cell lineage?
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.
What is the role of IL-7 in lymphocyte maturation?
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.
X-SCID
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.
What is the role of IL-15 in development of ILCs?
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.
Where are functional receptor genes for B/T cells developed?
Bone marrow for B cells, Thymus for T cells by gene rearrangement.
What are checkpoints? Why are they important?
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
pre-BCRs/pre-TCRs
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
Positive selection
The process by which lymphocytes that are non-pathogenic to self and that have useful receptors are chosen to continue on with maturation.
Positive selection for T Cells
In the T-Cell lineage, all T cells that recognize self MHC molecules continue on to maturation. (also express coreceptor CD8 or CD4)
Negative selection
the process that eliminates or alters developing lymphocytes whose antigen receptors bind strongly to self antigens present in the generative lymphoid organs.
Receptor editing
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
Clonal deletion
The process by which developing T/B cells with high affinity for self are eliminated by apoptosis
VDJ recombination
V- Variable region; D - Diversity region; J - Joining region. Three segments on chromosomes that are responsible for the generation of diverse receptors on lymphocytes
D segments are not found in what type of Ig chain?
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)
What are the sources of hyper-variability in receptors?
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
CDR3
Complementarity-determining region 3 variability in the junctional sequences between the V and D region and the D and the J region
How are the developmental stages of B lymphocytes distinguished from each other?
By distinct cell surface markers and a specific pattern of Ig gene expression.
Pro- B cell
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.
Pre-B cells
Developing B lineage cells that express the Ig u protein but have yet to rearrange their light chain loci.
pre-BCR
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)
BTK
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
