Ch. 9 T-Cell Development

Question 1

Where does T cell development begin in the body?

Answer 1

very early thymocyte development starts in the bone marrow

Question 2

Which cytokine is critical for developming HSCs into CLPs?

Answer 2

The cytokine IL-7 is critical for transitioning hematopoietic stem cells (HSCs) into common lymphoid progenitors (CLPs)

Question 3

Which receptor leads CLPs to the thymus?

Answer 3

Some undifferentiated thymocytes begin to express the receptor CD44 which is an adhesion molecule that allows cells to home to the thymus.

Question 4

Which ligand is critical for developing CLPs into TNKs?

Answer 4

notch ligand signaling

Question 5

CD44

Answer 5

an adhesion molecule (homing to the thymus)

Question 6

C-kit (CD117)

Answer 6

receptor for stem cell growth factor (keep undifferentiated cells alive)

Question 7

CD25

Answer 7

the a chain of the IL-2 receptor (important in key stages of T cell development)

Question 8

DN1

Answer 8

c-kit(CD117)++, CD44+, CD25-

Question 9

DN2

Answer 9

c-kit++, CD44+, CD25+

Question 10

DN3

Answer 10

c-kit+, CD44-, CD25+

Question 11

DN4

Answer 11

c-kit low/-, CD44-, CD25-

Question 12

Where does DN1 occur?

Answer 12

bone marrow to thymus

Question 13

Where does DN2 occur?

Answer 13

subcapsular cortex

Question 14

Where does DN3 occur?

Answer 14

subcapsular cortex

Question 15

Where does DN4 occur?

Answer 15

subcapsular cortex to cortex

Question 16

What is the outcome of pre-TCR signaling?

Answer 16

1. Suppression of further rearrangement of TCR β-chain & γ/δ-chain genes, resulting in allelic exclusion
2. Rapid proliferation in the subcapsular cortex
3. Cessation of proliferation
4. Initiation of TCRα chain rearrangement
5. Maturation to the DN4 stage (c-kitlow/−CD44−CD25−)

Question 17

Why does proliferation following pre-TCR signaling lead to increased binding diversity of T cells?

Answer 17

Because cells proliferate after successful β-chain rearrangement, & then stop alterations prior to making TCRα chain, we get a population of cells with the same β-chain & different α chains  BINDING DIVERSITY

Question 18

Function of αβ T cells

Answer 18

αβ T cells are the dominant participants in adaptive immunity & are primary found in SLOs

Question 19

Function of γδ T cells

Answer 19

γδ T cells are less understood, but appear to bridge adaptive & innate immunity & show up more in peripheral tissues

Question 20

Why are αβ T cells more common than γδ T cells (based on recombination successes)?

Answer 20

• To become an αβ T cell, only relies on successfully rearranging the β loci to form pre-TCR (and shut down rearrangement of γ & δ)
• To become a γδ cell, cell must successfully rearrange BOTH genes & produce two functional proteins
o Because of this, TCRαβ outcomes are more likely than TCRγδ

Question 21

On average, what percentage of T cells circulating in peripheral blood are γδ T cells?

Answer 21

5%

Question 22

Do γδ T cells progress to the DN4 stage of development? Why or why not?

Answer 22

No, Additionally, γδ only go through early thymocyte development, & leave the thymus after the DN2 or DN3 stage (when their TCR is rearranged)

Question 23

What goals have been accomplished at the end of early thymocyte development?

Answer 23

1. Hematopoietic cell precursors have expanded in the subcapsular cortex
2. Cells have committed to the T-cell lineage
3. Cells have “chosen” to become TCR-αβ or TCR-γδ T cells by recombining their TCR gene loci
4. TCR-γδ T cells have left the thymus & begin circulating
5. TCR-αβ cells express both CD4 & CD8 (DP cells)

Question 24

What is positive selection & what is the result for T cells of this selection process?

Answer 24

Positive selection selects thymocytes bearing moderate-affinity receptors capable of binding self-MC molecules, resulting in MHC restriction.

Question 25

What is negative selection & what is the result for T cells of this selection process?

Answer 25

Negative selection selects against thymocytes bearing high-affinity receptors for self-MHC/peptide complexes, resulting in self-tolerance.

Question 26

Positive selection is mediated by ________ cells in the thymic cortex.

Answer 26

cortical thymic epithelial cells

Question 27

___% of cells fail selection in the cortex.

Answer 27

95-98%

Question 28

What are the four possible outcomes of T cell selection in the cortex?

Answer 28

1. TCRs can’t bind; cells die by neglect 2. TCRs bind too strongly; negative selection (deletion) occurs 3. TCRs bind “just right”; positive selection to single-positive stage occurs 4. TCRs bind slightly more, making TREG cells

Question 29

What determines whether a DP T cell will develop into a CD4+ TH cell or a CD8+ TC cell?

Answer 29

TCR binding to MHC II, also binds with CD4, selecting the cell to the CD4+ subset ◦ TH cells The opposite happens if TCR binds MHC I, selecting the CD8+ subset ◦ TC cells

Question 30

Another round of negative selection is mediated by ________ cells in the thymic medulla.

Answer 30

Medullary thymic epithelial cells (mTECs)

Question 31

What is the purpose of AIRE expression in thymic epithelial cells?

Answer 31

Autoimmune regulator protein (AIRE) induces expression of many tissue-specific proteins in medullary thymic epithelial cells (mTECs)

Question 32

Dendritic cells also participate in negative selection in the medulla of the thymus. How are they able to do this?

Answer 32

Medullary dendritic cells can acquire mTEC antigens by engulfing mTECs and also participate in negative selection

Question 33

What is the end result of negative selection in the thymus?

Answer 33

Ensures self-tolerance

Question 34

Upregulation of the transcription factor ______ leads to three major outcomes that leads T cells towards the circulatory system and SLOs and keeps the cells alive.

Answer 34

Foxo1

Question 35

What genes are upregulated by Foxo1 ?

Answer 35

- Sphingosine-1-phosphate receptor - IL-7R - CCR7

Question 36

Sphingosine-1-phosphate receptor (S1PR)

Answer 36

required to help T cells travel to the circulatory system and inflamed tissues

Question 37

IL-7R

Answer 37

gives survival signals to mature T cells (cytokine)

Question 38

CCR7

Answer 38

a chemokine receptor that helps cells exit and traffic to lymph nodes

Question 39

What are RTEs?

Answer 39

RTEs= recent thymic emigrants

Question 40

How does RTE activation compare to mature, naïve T cells?

Answer 40

o Not as functionally mature as older cells o Don’t proliferate or secrete cytokines as vigorously in response to TCR stimulation o An area of active research, but it appears that interactions in SLOs leads to maturation of RTEs to mature, naïve T cells in about 3 weeks

Question 41

About how long does it take for an RTE to mature into a fully functional naïve T cell?

Answer 41

about 3 weeks

Question 42

How do Treg cells inhibit adaptive immune responses?

Answer 42

1. Deplete the local area of stimulating cytokines 1. Produce inhibiting cytokines 1. Inhibit APC activity (inhibit their maturation) 2. Directly kill T cells

Question 43

What transcription factor is upregulated in T cells to make the TREG cells?

Answer 43

FoxP3

Question 44

How is tolerance maintained in the periphery for cells that escape negative selection in the thymus?

Answer 44

Peripheral mechanisms of tolerance also protect against autoreactive thymocytes ◦ Some self-antigens are “hidden” because only pAPCs express the correct costimulatory molecules needed to initiate immune responses ◦ Autoreactive naïve T cells can see the MHC/self-peptide complex on other cells, but won’t receive correct costimulatory signals

Question 45

What is "anergy"?

Answer 45

high-affinity interactions without costimulatory ligands