T Cell Development Flashcards
T and B cells develop from BLANK cells
T and B cells develop from haematopoietic stem cells (HSCs)
If T cells respond to self peptides then this leads to BLANK
If T cells respond to self peptides then this leads to autoimmunity
How do T cells produce a useful repertoire of cells? (i.e. do not recognise self peptides, but do recognise foreign antigens)
TCR gene rearrangements are completely random, therefore there are T cells with antigen receptors that can recognise self MHC molecules.
There is strong selection against T cells that have
high reactivity against self peptides as these will
cause autoimmunity. Negative Selection. These cells die.
There is a selection for T cells that DON’T recognise self peptides/self MHC. Positive selection. These cells survive and are ready to fight infection.
Thymocytes are homogenous/heterogenous for expression of the MHC receptors CD4 and CD8
Thymocytes are heterogenous for expression of
the MHC receptors CD4 and CD8
Thymus development is controlled by distinct/overlapping antigen receptor and cytokines
Thymus development controlled by overlapping antigen receptor and cytokines
T cell development overview:
The first stage of T cell development in the thymus is
rearrangement of one TCR beta allele. This occurs in T cell precursors that enter from bone marrow and which do not express the MHC receptors CD4 and CD8 and hence are called double negative (DN) thymocytes.
Cells that successfully rearrange a TCR beta allele will express a functional receptor complex known as the pre-TCR comprising a TCR beta chain, a subunit known as pre T alpha, and the signalling subunits of the CD3 antigen.
When the pre TCR is expressed at the cell membrane it
promotes cell survival and entry into the cell cycle. It also downregulates Rag gene expression to prevent rearrangement of the 2nd TCR beta allele.
Hence all T cells in the periphery express a TCR beta allele of single specificity. This process is known as allelic exclusion.
Cells that express a functional pre TCR then undergo
massive proliferative expansion and differentiate into cells that co-express CD4 and CD8 and hence are called
CD4+CD8+ double positive (DP) cells. DP cells re-express Rag genes and start to rearrange their TCR alpha genes.
preTCR:
Cells that successfully rearrange a TCR beta allele will express preTCR
Comprised of a TCR beta chain, a subunit known as pre T alpha, and the signalling subunits of the CD3 antigen.
At the membrane the preTCR induces survival, proliferation, and differentiation and induces the cells to upregulate CD4 and CD8. Also downregulates Rag gene expression to prevent rearrangement of the 2nd TCR beta allele.
The preTCR does not need a ligand to signal- just expression at the membrane is all that is required.
The expression of all subunits is needed to stabilize this
complex at the cell membrane.
Beta selection:
Pre T cells express the invariant signaling chains of a receptor known as the preTCR complex in their cytosol (pre T alpha, and CD3s)
Random beta chain rearrangements occur involving complex DNA break/repair mechanisms.
The cell thinks it has damaged DNA and activates cell death pathways.
If a productive b chain protein is made it pairs with the pre T alpha allows expression of preTCR
at the plasma membrane. The preTCR then signals further T cell development. If the cell does not express a beta chain protein it dies.
3 Phases of B Cell Development
- Repertoire Assembly
- Negative Selection
- Positive Selection
Developing B cells are programmed to die by apoptosis unless they are rescued by BLANKS from BLANKS
Developing B cells are programmed to die by apoptosis unless they are rescued by survival signals from productively assembled pre-BCR and mature BCR complexes.
Only if a developing B cell successfully completes V(D)J gene rearrangement to produce functional Igµ/d and Igk/l proteins can it survive and continue to develop
