Chapter 7 Part 2 - Development of T lymphocytes Flashcards
recap: how is a large Pre-T cell formed?
by the successful assembly of a pre-T cell receptor
(superdimer, CD3/Zeta chain signaling complex)
Explain what happens to Large Pre-T cells
-they are induced to proliferate (clonal expansion)
-they begin to express CD4 and CD8 (double positive DP thymocytes)
where are large double positive thymocytes located?
in the inner cortex of the thymus, where they are enmeshed in cortical epithelial cells
What happens to large double positive thymocytes?
they divide to produce small double positive thymocytes
after productive rearrangement of a beta chain…..
RECOMBINATION IS SILENCED – allelic exclusion
after productive rearrangement of a beta chain, recombination machinery is silenced.
when is it reactivated?
when large DP lymphocytes divide to produce small DP lymphocytes.
Rearrangements occur at alpha, gamma, and delta loci. NOT BETA
When the recombination machinery is reactivated. rearrangements occur at alpha, gamma, and delta loci. (NOT BETA)
which rearrangement is favored?
alpha rearrangement is favored because you can have SUCCESSIVE rearrangements at both alpha chain loci. the gene structure allows for MANY successive rearrangements
____% of thymocytes make a successful a:B TCR
> 90%
the alpha chain locus can sustain ____ attempts at a functional rearrangement
many
with productive rearrangement at alpha chain…
all delta gene segments are excised out, EVEN IF there was a productive rearrangement
this reduces the possibility of generating a gamma:delta T cell
thus, the a:b T cell population is more numerous than gamma:delta T cells
explain the steps of T cell development under a DOUBLE NEGATIVE thymocyte – assume Beta chain is rearranged first
- Committed T cell progenitor
- Rearrange B, gamma, delta
- First checkpoint – surrogate light chain with beta chain (pre-TCR)
- Large Pre-T cells proliferate
Explain the steps of T cell development under a DOUBLE POSITIVE thymocyte.(assume B chain is selected)
- Large Pre T cells proliferate (express CD8 and CD4) and divide to form small Pre-T cells.
- Rearrange alpha, delta, and gamma
- second checkpoint (for TCR)
the process of T cell development is happening in the cortex or medulla of the thymus?
cortex
now, we have immature T cells expressing a:B TCR complex, CD4, and CD8.
now we will test for what? (second checkpoint)
test for the ability to bind peptide: MHC complexes.
there are TWO selection processes:
positive selection – favors binding self peptide:MHC complexes
negative selection: eliminates autoreactive T cells
This positive/negative selection ONLY involves:
a:B t cells.
the development of gamma:delta T cells is incomplete
approximately what % of DP thymocytes have T cell receptors that can bind to MHC Class 1 or MHC Class 2 molecules?
very small –2%
positive selection identifies….
the T cells that can bind MHC’s
when does positive selection begin?
a few hours after the assembly of a functional alpha:beta TCR
Moderate or strong binding of TCR’s to MHC produces a ____ signal
Weak or no binding at all…
moderate or strong binding produces a SURVIVAL signal
weak or no binding of MHC at all results in death by apoptosis
in the absence of infection, what are MHC molecules presenting?
SELF ANTIGEN
what is presenting the self peptide: MHC complexes to T cells to test them?
cortical epithelial cells (epithelial cells in the cortex)
one individual MHC can present approximately how many different peptides?
~10,000 different peptides
with _____ major polymorphic HLA genes on homologous chromosomes, ~_______ self-peptides can be presented to _____ different MHC molecules
with SIX major polymorphic HLA genes on homologous chromosomes, ~120,000 self-peptides can be presented to TWELVE different MHC molecules
HLA-A
HLA-B
HLA-C
HLA-DP
HLA-DQ
HLA-DR
(all x2 bc there are 2 chromosomes)
if the binding of T-cell receptor to self:MHC molecule occurs within ____ days of functional T-cell receptor production, the thymocyte will continue to develop
3-4 daus
what happens if the T-cell receptor does NOT binf to self peptide:MHC?
rearrangement of alpha chain can continue
if all steps proceed smoothly, positive selection can occur within ____ of thymocyte entering the thymus
a few hours
” if all steps proceed smoothly, positive selection can occur within a few hours of thymocyte entering the thymus “
what does it mean by “all steps?”
productive beta chain, assembly of preTCR (superdimer), productive a chain, and assembly of T cell receptor
explain what happens if successive recombination at the alpha locus is necessary
rearrangement occurs on BOTH loci.
this creates the potential for generation of 2 alpha chains and thus 2 T-cell receptors, which is VERY RARE
one of the 2 TCR’s is usually not functional.
explain the difference between receptor editing for B cells and T cells
they are analogous to each other
the difference is that in B cell editing, it is trying to get RID of the reactivity against self antigens, including MHC, whereas T cell uses receptor editing to acquire reactivity to self MHC
immunoglobulins contain 2 or more heavy and light chain genes to preserve their functional integrity.
However, T cells only have ONE alpha chain.
what does this mean?
it is CRUCIAL for allelic exclusion to exist for immunoglobulins. Without it, the BCR would be essentially not functional.
however, allelic exclusion of TCR for the alpha chain is not necessary, because there’s only one alpha chain in the TCR
Self peptide: MHC complexes present antigen to…
DP thymocytes (double positive)
the positive selection (self peptide: MHC complex binding to DP thymocyte) results in the generation of……
EXPLAIN
SINGLE, POSITIVE THYMOCYTES
if the DP thymocyte binds MHC Class I, CD8 is recruited into the signaling complex and the cell becomes COMITTED to expressing CD8
cd4 is restricted
if the DP thymocyte binds MHC Class II, CD4 is recruited into the signaling complex and the cell becomes COMMITTED to expressing CD4
cd8 is restricted
recap:
CD8 only reacts with MHC Class ____
CD4 only reacts with MHC Class ___
CD8 — MHC CLASS 1
CD4 — MHC CLASS 2
