Chapter 7 Part 1 -- Development of T lymphocytes Flashcards
T cells derive from what precursor
common lymphoid precursor
true or false
T cells are similar to B cells in their gene rearrangements
true
how many distinct lineages do T cells have? name them
2:
a:B T cell
gamma:delta T cell
where does T cell development take place?
in the thymus
what are “thymus dependent lymphocytes”?
T cells
future T cells leave the bone marrow as ___ and travel through circulation to the _____
future T cells leave the bone marrow as UNCOMITTED STEM CELLS (cd34+ precursors)and travel through circulation to the THYMUS
recap: pluripotent hematopoetic stem cells express ___ ONLY
CD34
CD34+ precursors (hematopoetic stem cell precursors) enter the thymus where?
enter the thymus at the border of the cortex and medulla through the HEV (high endothelial venule)
CD34+ precursors that have entered the thymus go where in the thymus?
they become embedded in stromal cells in the epithelium of the thymus
T cell precursors travel from the ____ to develop in the _____
travel from the BONE MARROW to develop in the THYMUS
Mature T cells leave the thymus and travel to _____
secondary lymphoid tissues
explain the anatomy of the thymus
has a right lobe and a left lobe, septa, and a lobule.
located above the heart and between the lungs
the thymus is a ____ lymphoid organ
PRIMARY
is the thymus involved in lymphocyte recirculation?
no
does the thymus receive lymph from other tissues?
no – not connected to the lymphatics
what is located in the CORTEX of the thymus?
-immature T cells (called thymocytes)
-cortical epithelial cells
-macrophages
what is located in the MEDULLA of the thymus?
-mature thymocytes
-medullary epithelial cells
-dendritic cells
-macrophages
-Hassall’s corpuscles
what are hassall’s corpuscles?
concentrically arranged epithelial cells
when in life is the thymus FULLY DEVELOPED?
at birth
when does the thymus begin to degenerate?
1 year after birth
what does involution mean
shrinkage of an organ with age
The thymus begins to degenerate 1 year after birth.
explain how this happens
the thymocyte area (immature T cells in the cortex) is replaced by fat
called the INVOLUTION of the thymus
does the reduction of functional thymus making T cells, or loss of the thymus in adults (thymectomy) affect T-cell mediated immunity?
no
upon entering the thymus, what happens to T cell precursors?
T cell precursors contact stromal epithelial cells within the thymus.
this provides signals for proliferation and differentiation
the commitment of T cell precursors to T cell lineage is driven by……
IL-7 (cytokine)
and Notch Signaling
after how long in the thymus do T cell precursors have a commitment to T cell lineage?
~1 week
what is the term for those T cell precursors that have spent ~1 week in the thymus and are now committed to T cell lineage?
DN thymocytes (double negative thymocytes)
because they lack both CD4 and CD8 expression
what are DN thymocytes doing?
beginning to rearrange their gene segments
explain the beginnings of the rearrangements of T cells
Begin CONCURRENTLY at gamma, delta, and beta loci. NO RESTRICTION to a particular locus
how is it determined if gamma:delta is made or alpha:beta is made?
a RACE to make productive rearrangements.
if gamma and delta chains are made first, the T cell is committed to gamma:delta T cell
if B chain is produced first, STILL NOT COMMITTED.
the Beta chain is incorporated into the Pre T cell receptor. rearrangements halt and proliferation begins. CD4 and CD8 are expressed. Called DP THYMOCYTES (double positive) bc both CD4 and CD8 are expressed
rearrangements halt while the B chain is incorporated into the Pre T cell receptor.
when do rearrangements begin again?
at the DP thymocyte stage.
rearrangement of alpha chain genes is now allowed, and rearrangement at gamma and delta chain genes also continues.
if a:B TCR is produced first, the cell commits to a:B lineage as a committed a:B T cell (PRE T CELL)
IF a:B TCR is produced first, the cell commits to a:B lineage as a committed a:B T cell.
what is the term for this cell?
a pre-T cell
failure to make any productive rearrangements results in ___________.
apoptosis
these dead cells are cleared by macrophages
is there a lot to “clean up” due to the apoptosis of cells with unproductive rearrangements? explain
YES there is a lot for the macrophages to clean up.
this is so bc only around 2% of thymocytes ultimately survive
explain the differences in the paths of double negative T cells.
double negative T cell undergoes a RACE to make productive rearrangements.
if gamma: delta chain genes rearrange, a gamma:delta receptor assembles. this receptor signals to STOP FURTHER REARRANGEMENTS and is COMMITTED to gamma:delta lineage.
the gamma:delta T cell then matures, leaves the thymus, and migrates to the peripheral tissues
if the Beta chain gene rearranges first, it is not yet fully committed to alpha:beta lineage.
A pre T cell receptor assembles, which signals to STOP REARRANGEMENT and induce the proliferation and expression of CD4 and CD8 (double positive thymocyte)
the Pre-T cell then resumes rearrangement of ALPHA, gamma, and delta genes. Race to see which it will be
in double negative thymocyte rearrangement, either ___ or ____ will be produced
pre gamma:delta T cell receptor or pre-T cell receptor (if beta rearranges first)
explain what happens if the Double Negative thymocyte rearranges gamma and delta first
the gamma and delta chains are produced and assemble with CD3/Zeta chain signaling complex that gets moved to the cell surface and signals to STOP BETA CHAIN REARRANGEMENT. fully committed to gamma:delta T cell lineage.
the fully mature gamma:delta T cell exits the thymus and enters circulation
Explain what happens if the double negative thymocyte rearranges the beta chain first
the Beta chain is produced and moved to the ER.
there, it is tested for its ability to bind SURROGATE ALPHA CHAIN (called PTa(lpha) – it’s an invariant peptide.
if the binding is successful, the complex will assemble with CD3/zeta chain signaling complex to form a PRE-T CELL RECEPTOR
Pre-T cell receptor consists of:
-2 beta chains and 2 pta molecules. called a SUPERDIMER
the pre-T cell receptor consists of 2 beta chains and 2 pta molecules. It is called a superdimer.
this complex serves as….
a stringent TEST of beta chain conformation and its capacity to form a T-cell receptor.
the super dimer (2 beta chains and 2 pta molecules) bonding sends signals to do what?
the binding of the superdimer sends signals to halt gene segment rearrangements
the formation of the superdimer is a CHECKPOINT. if the checkpoint is successfully passed, what happens?
a pre-T cell receptor forms. (2 beta chains + 2 pta molecules + CD3/Zeta chain signaling complex)
if the superdimer checkpoint fails, what happens?
cell death
productive rearrangements favor which chain fate?
why? give the approximate success rate
beta chain
-there are TWO constant regions in the Beta locus. enables successive rearrangements
-2 loci on homologous chromosomes
4 total chances to rearrange Beta chin
~80% success rate
the successful assembly of a pre-T cell receptor produces a….
this process is governed by…
LARGE PRE T CELL
allelic exclusion
