Development of T Lymphocytes (1/4) Flashcards
How long is T cell development & where does it take place?
What cells do you start out with?
Takes 3 weeks & it occurs in the thymus
You start with progenitors that are derived from pluripotent bone marrow cells. Early thymocytes lack CD4 or CD8 but aren’t committed to the T-cell lineage– can become B cells and NK cells
What cells are in the 2 main histological regions of the thymus?
Peripheral cortex: densely populated with lymphoid cells; positive selection occurs here; this is where most of T-cell development occurs
Central medulla: less lymphocyte rich, contains dendritic cells & macrophages, which are the main mediators of negative selection
Which signals promote T-cell development?
Signals from the stroma i.e. NOTCH1 promote T-cell commitment, differentiation & proliferation
What happens in the case of loss of lymphoid progenitors? What about loss of thymic stroma?
Both have loss of T cells!
If no lymphoid progenitors: you get SCID
Defects in thymic epithelial cells = “nude” mice because they have no hair :(
Note that you can use marrow from nude mice to rescue the phenotype of SCID mice. You can use thymus cells from SCID mice to rescue phenotype of nude mice.
Note that the opposite wouldn’t work!!
What is a DN cell?
Double Negative: it’s an early stage T cell that has no CD4 nor CD8; not committed to the T cell lineage
What are the stages of DN development?
What signals drive their development?
What are the 2 types of T cells?
Alpha beta: most abundant, responsible for adaptive immune response, have alpha beta TCR on surface
Gamma delta: minor population, recognizes lipid antigens in the gut, spans innate/adaptive immune response, gamma delta t-cell receptor on surface
How do T cells decide whether to become gamma delta or alpha beta?
They are all rearranged at the same time & the outcome is due to a competition of signals.
A strong signal is required for a successful gamma-delta rearrangement. A weaker preTCR signal drives alpha-beta lineage
When does rearrangement of the TCR genes occur?
At the same time as alpha-beta T-cell development (beta- chain rearrangement starts & ends wtih DN development stages 1-4). DJ joined in DN2, V joins DJ in DN3.
TCR alpha chain rearrangement occurs in double positive cells
What is a preTcell receptor?
It’s a protein complex that includes the beta chain, preTalpha, which assembles with CD3 complex and another protein
Assembly is required to halt rearrangement of beta, gamma and delta genes
Its assembly is sufficient for signalling (doesn’t need to bind anything) = just like the preBcell receptor
It’s a checkpoint in T cell development- if cell passes, it’s called a pre-T cell
Also drives expression of CD4 and CD8
Generates a pool of cells with a single beta change that will go on to rearrange the alpha chain. Ultimately results in <5% of these cells surviving & also these can have same beta chain but different alphas
What occurs during TCR alpha rearrangement?
Only VJ segments rearrange
Only occurs after successful beta rearrangement
60J segments & lots of V segments –> multiple rounds of recombination
Note that alpha rearrangement always eliminates the linked delta chain locus
What is recombination?
Alpha locus will recombine until it gets a functional TCR
This occurs after rearrangement.
If you get a self recognizing complex during recombination, then it’s blocked during positive selection because DP cells live only 3-4 days unless rescued by TCR stimulation & positive selection
What is T-cell selection?
The process of rescue from cell death and maturation ot SP CD4 or SP CD8 cells upon recognition of MHC-self peptides
Negative selection TCR that respond too strongly to self peptide are eliminated as potentially self-reactive
What is positive selection & where does it occur?
Survival signal allows DP cells to mature to CD4/8 if they can recognize self MHC in cortical cells in thymus. It’s coupled with CD4/8 cell fate specification
Only occurs in the cortex
It’s the encounter of a DP T cell that encounters an epithelial cell expression MHC I or II peptide
Successful interaction –> positive selection & generates CD8 (when it encounters MHC I) or CD4 (when it finds MHC II)
Unsuccessful –> continuous rearrangement of alpha to try making a TCR again
Most DP cells fail positive selection and die by apoptosis
