T Cell Development

Question 1

Where do T cell precursors originate?

Answer 1

In the Bone marrow

Question 2

Where do the T cells develop?

Answer 2

The thymus

T cells at different stages of development are associated with specific reigons

Question 3

Thymocytes

Answer 3

Developing T cells in the thymus

Question 4

How long does T cell development take?

Answer 4

1-3 weeks

Question 5

Describe the early stages of T cell development.

Answer 5

• TCR independent
• precursors come from bone marrow and develop in the thymus
• TCR rearrangments begin and occur in an ordered progression

Question 6

Decribe the ordered progession of TCR rearrangments.

Answer 6

• beta chain happens before alpha chain
• must make functional rearrangments

Question 7

Describe the late stages of T cell development.

Answer 7

TCR dependent

has positive selection, negative selection and lineage commintment

Question 8

Double negative 1 cells (DN1)

Answer 8

T cell precursors that leave the bone marrow and are being directed to the thymus via chemokines

they also lack CD4 and CD8

Question 9

DN2

Answer 9

in the subcapsular cortex and are doing TCR rearrangments. These cells have commited to T cell fate

Question 10

DN3

Answer 10

In the subcapsular cortex and express the pre-TCR and beta selection is occuring

Question 11

DN4

Answer 11

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

Question 12

WHat transcription factors are accosiated with commintment to T cell lineage?

Answer 12

Notch and GATA-3

Question 13

beta selection

Answer 13

Selection for a functional beta chain that can form the pre-TCR

Question 14

What does the pre-TCR consist of (structure)?

Answer 14

has a beta chain, pre-Talpha, and CD3 signalling subunits

Question 15

What cells express the pre-Talpha?

Answer 15

all DN3/4 cells

Question 16

Double positive thymoscyte

Answer 16

has a alpha/beta TCR expressed on the surface with both CD4 and CD8

about 80% of thymocyte population
present in the cortex

Question 17

How d T cells recodnize Ag?

Answer 17

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

Question 18

MHC registration

Answer 18

Developing thymoscytes learn what is self MHC and become restricted to recodnize peptides in the context of self MHC

Question 19

What are the 4 fates of DP thymocytes if they have an affinity for self MHC plus self-peptide?

Answer 19

1. 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)
2. Positive selection (have an intermediate affinity for self MHC+ peptide but wont cause autoimmunity, the “educators”)
3. Agonist selection (some are strongly reactive and they adopt a different fate such as Tregs which help turn off immune responses)
4. 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)

Question 20

Why are so many thymoscytes lost by death by neglect?

Answer 20

The TCR gene rearrangments are random and more likely that the TCR will have little to no affinity for self Ag

Question 21

How does a DP cell become a single positive cell?

Answer 21

• lineage commitment where different transcription factors mediate differenciation

CD4: Thpok
CD8: Runx3

Several models for this: instructive, stochastic…

Question 22

Instructive model

Answer 22

• 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

Question 23

Stochastic model

Answer 23

Cells randomly down-regulate CD4 or CD8

Question 24

Negative selection in the medulla characteristics

Answer 24

• 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

Question 25

AIRE

Answer 25

autoimmune regulator taht opens up chromatin in the tissue restricted Ags and allows them to be transcribed

Question 26

APECED

Answer 26

Immunedeficiency that manifests as autoimmunity

T cells reactive to tissue restricted self Ag are not deleted in the thymus