Chapter 7 Part 2 - Development of T lymphocytes

Question 1

recap: how is a large Pre-T cell formed?

Answer 1

by the successful assembly of a pre-T cell receptor
(superdimer, CD3/Zeta chain signaling complex)

Question 2

Explain what happens to Large Pre-T cells

Answer 2

-they are induced to proliferate (clonal expansion)
-they begin to express CD4 and CD8 (double positive DP thymocytes)

Question 3

where are large double positive thymocytes located?

Answer 3

in the inner cortex of the thymus, where they are enmeshed in cortical epithelial cells

Question 4

What happens to large double positive thymocytes?

Answer 4

they divide to produce small double positive thymocytes

Question 5

after productive rearrangement of a beta chain…..

Answer 5

RECOMBINATION IS SILENCED – allelic exclusion

Question 6

after productive rearrangement of a beta chain, recombination machinery is silenced.
when is it reactivated?

Answer 6

when large DP lymphocytes divide to produce small DP lymphocytes.

Rearrangements occur at alpha, gamma, and delta loci. NOT BETA

Question 7

When the recombination machinery is reactivated. rearrangements occur at alpha, gamma, and delta loci. (NOT BETA)
which rearrangement is favored?

Answer 7

alpha rearrangement is favored because you can have SUCCESSIVE rearrangements at both alpha chain loci. the gene structure allows for MANY successive rearrangements

Question 8

____% of thymocytes make a successful a:B TCR

Answer 8

> 90%

Question 9

the alpha chain locus can sustain ____ attempts at a functional rearrangement

Answer 9

many

Question 10

with productive rearrangement at alpha chain…

Answer 10

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

Question 11

explain the steps of T cell development under a DOUBLE NEGATIVE thymocyte – assume Beta chain is rearranged first

Answer 11

1. Committed T cell progenitor
2. Rearrange B, gamma, delta
3. First checkpoint – surrogate light chain with beta chain (pre-TCR)
4. Large Pre-T cells proliferate

Question 12

Explain the steps of T cell development under a DOUBLE POSITIVE thymocyte.(assume B chain is selected)

Answer 12

1. Large Pre T cells proliferate (express CD8 and CD4) and divide to form small Pre-T cells.
2. Rearrange alpha, delta, and gamma
3. second checkpoint (for TCR)

Question 13

the process of T cell development is happening in the cortex or medulla of the thymus?

Answer 13

cortex

Question 14

now, we have immature T cells expressing a:B TCR complex, CD4, and CD8.

now we will test for what? (second checkpoint)

Answer 14

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

Question 15

This positive/negative selection ONLY involves:

Answer 15

a:B t cells.

the development of gamma:delta T cells is incomplete

Question 16

approximately what % of DP thymocytes have T cell receptors that can bind to MHC Class 1 or MHC Class 2 molecules?

Answer 16

very small –2%

Question 17

positive selection identifies….

Answer 17

the T cells that can bind MHC’s

Question 18

when does positive selection begin?

Answer 18

a few hours after the assembly of a functional alpha:beta TCR

Question 19

Moderate or strong binding of TCR’s to MHC produces a ____ signal

Weak or no binding at all…

Answer 19

moderate or strong binding produces a SURVIVAL signal

weak or no binding of MHC at all results in death by apoptosis

Question 20

in the absence of infection, what are MHC molecules presenting?

Answer 20

SELF ANTIGEN

Question 21

what is presenting the self peptide: MHC complexes to T cells to test them?

Answer 21

cortical epithelial cells (epithelial cells in the cortex)

Question 22

one individual MHC can present approximately how many different peptides?

Answer 22

~10,000 different peptides

Question 23

with _____ major polymorphic HLA genes on homologous chromosomes, ~_______ self-peptides can be presented to _____ different MHC molecules

Answer 23

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)

Question 24

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

Answer 24

3-4 daus

Question 25

what happens if the T-cell receptor does NOT binf to self peptide:MHC?

Answer 25

rearrangement of alpha chain can continue

Question 26

if all steps proceed smoothly, positive selection can occur within ____ of thymocyte entering the thymus

Answer 26

a few hours

Question 27

” 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?”

Answer 27

productive beta chain, assembly of preTCR (superdimer), productive a chain, and assembly of T cell receptor

Question 28

explain what happens if successive recombination at the alpha locus is necessary

Answer 28

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.

Question 29

explain the difference between receptor editing for B cells and T cells

Answer 29

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

Question 30

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?

Answer 30

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

Question 31

Self peptide: MHC complexes present antigen to…

Answer 31

DP thymocytes (double positive)

Question 32

the positive selection (self peptide: MHC complex binding to DP thymocyte) results in the generation of……

EXPLAIN

Answer 32

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

Question 33

recap:

CD8 only reacts with MHC Class ____
CD4 only reacts with MHC Class ___

Answer 33

CD8 — MHC CLASS 1
CD4 — MHC CLASS 2