T Cell Development l Flashcards
Where do T cells originate and develop?
originate = bone marrow
develop = thymus
What are developing T cells referred to as?
thymocytes
How long does T cell development take?
1-3 weeks
Describe the size of the thymus as human development occurs.
at birth = thymus is fully developed
at peak puberty = thymus at greatest size
after peak puberty = thymus atrophies
Describe the lobular structures of the thymus
lobular structures are seperated by a capsule, each capsule contains an outer cortex and an inner medulla
What are some characterisitics/events of early T cell development?
- TCR independent
- precursors come from bone marrow and develop in the thymus
- TCR rearrangement begins in an ordered progression
- expansion of T cell precursors that successfully rearrange the TCR beta chain and can form the pre-TCR (beta selection)
What are some characteristics/events of late T cell development?
- TCR dependent
- positive selection
- negative selecton
- CD4+ or CD8+ lineage commitment
What is positive selection?
selection for cells whose TCRs can interact with self-MHC/self-peptides with intermediate affinity
What is negative selection?
selection against cells with TCRs that strongly interact with self-MHC/self-peptides
What is CD4+ or CD8+ lineage commitment?
thymocytes become CD4+ or CD8+
What are some other names for T cell precursors?
- thymus-settling progenitors (TSPs)
- double negative 1 (DN1) cells
How are T cell precursors directed to the thymus?
via cytokines
What are DN stages defined by?
lack of CD4 and CD8 expression
How are the four DN stages distinguished?
by cell surface markers
At what stage can T cell precursors no longer give rise to other lineages?
DN2
What TFs are expressed when a T cell commits?
Notch and GATA-3
At what DN stage does Beta selection occur?
DN2
Describe the ordered progression of TCR rearrangements
- beta chain and delta and gamma chain start rearranging
- if beta chain has a successful rearrangement, the alpha chain will begin rearranging
- if both the delta and gamma chain successfully rearrange before the beta chain, the T cell will become a gamma/delta T cell
At what stage is the pre-TCR expressed, and what is the pre-TCR?
stage = starts at DN3 and continues into DN4
pre-TCR = functional beta chain + pre-Talpha + CD3
What is beta selection?
selection for a functional beta chain that can bind pre-Talpha and form the pre-TCR
What stage of B cell development does beta selection resemeble?
pre-B cell stage -> functional rearrangement of the H chain
How does pre-TCR signaling occur?
Ligand-independent: expression of the pre-TCR on the surface is sufficient for pre-TCR signaling
What are the four developmental signals that the pre-TCR provides?
- cell becomes permissive for TCR alpha chain locus rearrangment
- stimulates expression of CD4 and CD8
- stimulates proliferation
- stops additional TCR beta chain locus rearrangements (allelic exclusion)
What are the defining features of a DP T cell? And where are these cells found
alpha/beta TCR expressed on the surface with both CD4 and CD8
found in the cortex of the thymus
What are the important checkpoints that occur at the DP stage?
- positive selection
- negative selection
- lineage commitment
What is education?
The process of positive and negative selection in the thymus
Why do T cells have to go under education?
T cells recognize Ag in the context of self-MHC; therefore, they must have TCRs that bind self-MHC, but at the same time not cause autoimmunity
What cells mediate positive selection of thymocytes?
corticol thymic epithelial cells (cTECs)
What is MHC restriction?
developing thymocytes learn what is self MHC and become restricted to recognize peptides in the context of self-MHC
What cells mediate negative selection?
cTECs and DCs
What process in T cell development is an example of central tolerance?
Negative selection in the thymus
Describe the experimental evidence for cTECs mediating MHC restricition. What was the conclusion made?
- H2a/a mother and a H2b/b father (haplotypes) were crossed
- the H2a/b progeny had their thymus removed and exposed to lethal x-radiation which removed bone-marrow derived cells including HSCs
- A thymus that is H2b/b was irridated to remove the thymocytes (epithelial cells were not affected) and HSCs (H2a/b) were transplanted into the mice
- the mice were infected with LCMV (a virus)
- spleen cells which include mature T cells were removed and cultured on two plates: one where all the cells are H2a/a and one where all the cells were H2b/b, and each plate was infected with LCMV
- LCMV H2a/a cells were not killed, LCMV H2b/b cells were killed
conclusion: non-lymphoid cells of the thymus (cTECs) mediate MHC restriction
Describe the four different fates that T cells will fall into during education.
- death by neglect
- majority of cells
- little or no affinity
- cells undergo apoptosis - positive selection
- intermediate affinity
- 2-5% of cells - agonist selection
- some strong self-reactive thymocytes adopt a different fate
- Treg or other fates - negative selection
- strong affinity
- 2-5%
- most cells deleted through clonal deletion, but some anergy and receptor editing
Why are so many thymocytes lost by death by neglect?
TCR gene rearrangements are random; therefore, more likely that a TCR will have little to no affinity for self-MHC + self-peptide
