T Cell Development Flashcards
Where do T cell precursors originate?
In the Bone marrow
Where do the T cells develop?
The thymus
T cells at different stages of development are associated with specific reigons
Thymocytes
Developing T cells in the thymus
How long does T cell development take?
1-3 weeks
Describe the early stages of T cell development.
- TCR independent
- precursors come from bone marrow and develop in the thymus
- TCR rearrangments begin and occur in an ordered progression
Decribe the ordered progession of TCR rearrangments.
- beta chain happens before alpha chain
- must make functional rearrangments
Describe the late stages of T cell development.
TCR dependent
has positive selection, negative selection and lineage commintment
Double negative 1 cells (DN1)
T cell precursors that leave the bone marrow and are being directed to the thymus via chemokines
they also lack CD4 and CD8
DN2
in the subcapsular cortex and are doing TCR rearrangments. These cells have commited to T cell fate
DN3
In the subcapsular cortex and express the pre-TCR and beta selection is occuring
DN4
In the subcapsular cortex and is travelling to the cortex. At this stage they are proliferating, allelic exclusion of beta chain locus, the alpha chain locus rearrangment begins and becomes a DP thymocyte
WHat transcription factors are accosiated with commintment to T cell lineage?
Notch and GATA-3
beta selection
Selection for a functional beta chain that can form the pre-TCR
What does the pre-TCR consist of (structure)?
has a beta chain, pre-Talpha, and CD3 signalling subunits
What cells express the pre-Talpha?
all DN3/4 cells
Double positive thymoscyte
has a alpha/beta TCR expressed on the surface with both CD4 and CD8
about 80% of thymocyte population
present in the cortex
How d T cells recodnize Ag?
recodnize Ag in the context of self MHC therefore T cells must have TCRs that can bind self MHC plus self peptide to some degree
T cells undergo this eductation in the thymus
MHC registration
Developing thymoscytes learn what is self MHC and become restricted to recodnize peptides in the context of self MHC
What are the 4 fates of DP thymocytes if they have an affinity for self MHC plus self-peptide?
- Death by neglect (have no to low affinity for self-MHC+peptide and failed to be + selected so the cells are neglected and eventually undergo apoptosis)
- Positive selection (have an intermediate affinity for self MHC+ peptide but wont cause autoimmunity, the “educators”)
- Agonist selection (some are strongly reactive and they adopt a different fate such as Tregs which help turn off immune responses)
- Negative Selection (they have a strong affinity for self MHC and these cells are deleted through clonal deletion but some will anergy and receptor editing of alpha chain)
Why are so many thymoscytes lost by death by neglect?
The TCR gene rearrangments are random and more likely that the TCR will have little to no affinity for self Ag
How does a DP cell become a single positive cell?
- lineage commitment where different transcription factors mediate differenciation
CD4: Thpok
CD8: Runx3
Several models for this: instructive, stochastic…
Instructive model
- DP cells interact with cTECs expressing MHC I/II self peptides
- If TCR/CD8 recodnizes MHC I they are instructed to become CD8
- If TCR/CD4 recodnizes MHC II they are instructed to become CD4
Stochastic model
Cells randomly down-regulate CD4 or CD8
Negative selection in the medulla characteristics
- mediated by mTEC and some dendritic cells
- mTECs have an unusual ability to express proteins that are usually tissue restricted and allows T cells to be educated against tissue specific Ag before leaving the thymus
AIRE
autoimmune regulator taht opens up chromatin in the tissue restricted Ags and allows them to be transcribed
APECED
Immunedeficiency that manifests as autoimmunity
T cells reactive to tissue restricted self Ag are not deleted in the thymus
