T Cell Development

Front 1

In what organ do T cells rearrange genes?

Back 1

thymus

Front 2

What are the two distinct T cell populations?

Back 2

α-β and γ-δ

Front 3

What organ's major function is to ensure a person's mature T cells bear TCRs that recognize peptides in the context of the particular MHC Class I and II isoform?

Back 3

Thymus

Front 4

What are the 2 sublineages of α-β T cells, and which MHC Class do they recognize?

Back 4

1) CD4 Helpers : Recognize Class II

2) CD8 Killers : Recognize Class I

Front 5

What are immature T cells called in thymus?

Back 5

Thymocytes

Front 6

T/F Thymus receives lymph from other tissues.

Back 6

FALSE. As a primary lymphoid organ it is primarily concerned only with generating T cells, not with "using" them

Front 7

What happens in DiGeorge syndrome?

Back 7

Thymus fails to develop, T cells are absent, but wide susceptibility to wide range of opportunistic infections

Front 8

What is involution of the thymus?

Back 8

Process by which as person ages thymic tissue is gradually replaced by fat

Front 9

What do the macrophages in thymus do?

Back 9

Remove T Cells that fail to mature properly

Front 10

What are Hassall's corpuscles?

Back 10

Characteristic features of the medulla believed to be sites of cell destruction

Front 11

3 main stages of T Cell Development

Back 11

1) Entry of CD34+ stem cells from bone marrow --> Thymus --> Double negative stage (no CD4 or CD8)

2) Rearranging germ line T Cell receptor genes and positive selection

3) Negative selection

Front 12

What is the double negative stage?

Back 12

Cells express neither CD4 nor CD8

Front 13

What is the importance of IL7?

Back 13

Secreted by thymic stromal cells and binds to IL7 receptor on CD34+ progenitor cells. Stimulates differentiation into lymphoid progenitor cells.

Front 14

What's the role of Notch1?

Back 14

It's a surface membrane-associated receptor on thymocyte. It binds ligand on thymic epithelium --> induces change at expression level and <b>commitment to T cell lineage</b>

Front 15

How does Notch1 signaling occur?

Back 15

1) Notch1 Receptor (future T cell) and Notch1 Ligand (thymic epithelium) bind

2) Cleave of part of the Notch1 Receptor

3) Cleaved part goes to nucleus where it induces changes in transcription

4) Result is commitment to T cell lineage

Front 16

What types of receptors is the newly-committed thymocyte expressing?

Back 16

CD2; IL-7

Front 17

What are the lineages (4) a double-negative thymocyte can become?

Back 17

1) NK cell (innate immune response)

2) γ-δ T Cells

3) α-β : CD4 and CD8

4) Regulatory T cells (Treg)

Front 18

What's the role of regulatory T cells?

Back 18

pecialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens

Front 19

How does a T cell become either α-β or γ-δ?

Back 19

1) Starts with double negative precursor starting to rearrange β, γ, δ loci

EITHER of these things then happens

2) γ and δ rearrange forming a γ, δ receptor. It signals thru γ:δ receptor to stop further rearrangements.

2) &beta; chain rearranges, assembling a pre-TCR. Signals thru pre-TCR to stop rearrangement and induce proliferation and expression of CD4 and CD8

The &gamma; and &delta; loci are basically racing with &beta; to see who makes the first receptor. Whoever makes the first receptor wins.

Front 20

When is the &alpha; chain formed?

Back 20

After the &beta; cell has gotten expressed with a surrogate alpha (pT&alpha;)

During the double positive stage

Front 21

How many chances to make a successful rearrangement does the T cell get?

Back 21

4. Each allele gets 2 shots.

Front 22

What is pT&alpha;?

Back 22

The surrogate alpha chain

Front 23

What induces the pre-T cell to stop gene rearrangement?

Back 23

Successful rearrangement of a &beta; chain gene followed by signaling thru the pre-TCR --> suppresses expression of RAG

This ensures only one &beta; chain gene has a productive rearrangement --> allelic exclusion

Front 24

T cell receptor &alpha; genes are analogous to B cell receptor ___________ genes in that they're rearranged only after the others and have no D segments

Back 24

Light chain

Front 25

What other proteins are associated with the TCR?

Back 25

CD3 and &zeta;

Front 26

What are the 2 checkpoints in TCR development?

Back 26

1) pre-TCR with surrogate &alpha; chain (pT&alpha;)

2) Final TCR

Front 27

What initiates recombination of &alpha; locus?

Back 27

Coexpression of CD4 and CD8 (double positive stage)

Front 28

What stops recombination of the &beta;, γ, δ loci?

Back 28

expression of pre-TCR with surrogate α chain (pTα)

Front 29

What eliminates the possibility of becoming γ:δ t cell? How?

Back 29

Recombination of the &alpha; loci. This is because the &delta; locus is inside the &alpha; locus and will automatically get deleted.

Front 30

How is positive selection of thymocytes accomplished in thymus?

Back 30

Epithelial thymic cortex cells have lots of processes expressing MHC that reach out to &alpha;-&beta; T cells. If the TCRs can bind MHC, they survive. If not, they die by apoptosis.

Front 31

What determines whether T cell will be CD4 or CD8?

Back 31

If it binds to MHC Class I --> downregulates CD4 --> becomes CD8. Vice versa.

Front 32

What cell type mainly mediates negative T Cell selection?

Back 32

Bone marrow-derived antigen presenting cells

Front 33

What is AIRE (autoimmune regulator)?

Back 33

A transcription factor that causes several hundred rarely expressed genes (aka insulin made only Beta cells of pancreas) to be transcribed transiently by thymic epithelial cells. If T cells bind to them, they're also eliminated.

This expression then allows maturing thymocytes to become tolerant towards peripheral organs, thereby suppressing autoimmune disease.

Front 34

What is APECED syndrome?

Back 34

People affected lack AIRE, and thus do not eliminate self-reactive T cells in rarely expressed genes

Front 35

What drives negative selection?

Back 35

Peptide antigen.

Front 36

Where does negative selection take place in thymus?

Back 36

Near the cortico-medullary junction

Front 37

What are regulatory T cells?

Back 37

Subset of CD4 T cells that have TCRs specific for self antigen. They use FoxP3 for a transcriptional repressor protein.

When they contact self antigen, they respond by not proliferating but by <b>suppressing the proliferation of naive T cells responing to self antigens presented on the same antigen-presenting cell.</b>

Prevents the proliferation of autoreactive helper CD4 cells.

Front 38

What is FoxP3? What does a deficiency of this do?

Back 38

A unique transcriptional repressor expressed by regulatory T cells. Helps prevent naive autoreactive T cells from proliferation. Deficiency causes autoimmune disease, IPEX.

Front 39

What is IPEX?

Back 39

Autoimmune disease caused by lack of FoxP3

Front 40

How are positive and negative selection similar?

Back 40

Both involve interactions with complexes of peptides bound by Self-MHC molecules on thymic cell surface