Lecture 19 - Early T Lymphocyte Maturation Flashcards
What does the absence of a thymus result in?
DiGeorge syndrome, thymic aplasia
What happens to the thymus in puberty?
It involutes
What is the thymus made of in adults?
Mostly fat
Strange feature of mice without a thymus
They are bald. Mechanism unknown
Which type of organ is the thymus?
Parenchymous
How would you go about finding if new T cells are being made?
Search for excision circles of DNA.
Implies that RAG recombination is occurring
What happens to T cell development in puberty?
It drops dramatically, but doesn’t cease.
Some new T cells are made throughout life
How do thymocytes enter the thymus?
Through high endothelial venules
Which cells develop in the bone marrow and make their way to the thymus?
Thymocytes
What initiates T cell fate decision and proliferation in thymocytes?
Interaction with thymic stroma cells
Three principal fates of thymocytes
1) Alpha/beta T cells
2) Gamma/delta T cels
3) Invariant NK T cells
Alpha/beta T cells
Conventional T cells, further differentiate into CD4 or CD8
Gamma/delta T cells 1) 2) 3) 4)
1) Primarily located at epithelial, mucosal sites
2) Lack CD4, CD8
3) Don’t undergo positive or negative selection
4) Produced earlier in development than other T cells
What is T cell maturation tied to?
The histological structure of the thymus
What is the state of the TCR locus in thymocytes when they enter the thymus?
Germline configuration
Unrecombined
What happens in DN1?
TCR genes in germline configuration
DN2
Thymocytes become responsive to IL-2 (because of CD25 expression)
Beta-chain rearrangement commences (Dbeta - Jbeta joining)
DN3/4
Vbeta - DJbeta rearrangement
Pre-TCR testing tests whether cells express CD4 and CD8
DP
Rearrangement begins at the alpha chain locus
A single rearranged beta chain can combine with many different alpha chains
Cells important in thymocyte development
Cortical epithelial cells
Which loci do double-negative thymocytes rearrange
Gamma, delta, beta simultaneously
How do thymocytes become either alpha/beta or gamma/delta?
1)
2)
3)
1) If beta chain rearrangement is successful, pre-TCR is expressed (pTalpha is surrogate alpha chain)
2) This shuts of gamma/delta rearrangement
3) If beta chain doesn’t rearrange properly, gamma/delta rearrangement can continue
How does beta chain rearrangement shut off gamma/delta rearrangement?
1)
2)
1) Pre-TCR dimerisation induces proliferation
2) RAG shut down, allelic exclusion initiated, excision of gamma/delta genes
What is positive selection?
T cells are tested on their ability to bind self MHC
How does positive selection take place?
T cells live for 3-4 days and then die, unless rescued by TCR engagement with MHC
Which cells present MHC to DP thymocytes?
Thymic stromal cells (cortical epithelial)
What determines MHC restriction of thymocytes?
Cortical epithelial cells
What is negative selection for?
To prevent autoimmunity
How does negative selection occur?
1)
2)
1) Professional antigen presenting cells (DCs) present self peptides on MHC molecules to thymocytes
2) If TCR binds too strongly, thymocyte is phagocytosed
What is AIRE?
Generates antigens that look like self antigens (from genome)
Used to negatively select thymocytes
What is APECED?
Autoimmune polyendocrine syndrome
No AIRE
Leads to T cell infiltration of body sites, autoimmunity
How does lineage commitment take place? 1) 2) 3) 4)
1) Upon MHC signals, CD4 and CD8 are downregulated
2) CD4 is expressed at low levels. If it binds to MHCII, Lck activation enhances CD4, suppresses CD8
3) If CD4 doesn’t bind MHCII, CD8 binds MHCI, is upregulated
4) This results in single-positive T cells
Where do DN1 and mature T lymphocytes reside?
Medulla of thymus
Where are DN2, DN3/4 and immature double positive thymocytes?
Cortex of the thymus
