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Immunology > Ch. 9 T-Cell Development > Flashcards

Ch. 9 T-Cell Development Flashcards

1
Q

Where does T cell development begin in the body?

A

very early thymocyte development starts in the bone marrow

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2
Q

Which cytokine is critical for developming HSCs into CLPs?

A

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

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3
Q

Which receptor leads CLPs to the thymus?

A

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

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4
Q

Which ligand is critical for developing CLPs into TNKs?

A

notch ligand signaling

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5
Q

CD44

A

an adhesion molecule (homing to the thymus)

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6
Q

C-kit (CD117)

A

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

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7
Q

CD25

A

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

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8
Q

DN1

A

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

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9
Q

DN2

A

c-kit++, CD44+, CD25+

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10
Q

DN3

A

c-kit+, CD44-, CD25+

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11
Q

DN4

A

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

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12
Q

Where does DN1 occur?

A

bone marrow to thymus

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13
Q

Where does DN2 occur?

A

subcapsular cortex

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14
Q

Where does DN3 occur?

A

subcapsular cortex

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15
Q

Where does DN4 occur?

A

subcapsular cortex to cortex

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16
Q

What is the outcome of pre-TCR signaling?

A
  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−)
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17
Q

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

A

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

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18
Q

Function of αβ T cells

A

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

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19
Q

Function of γδ T cells

A

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

20
Q

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

A

• 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

21
Q

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

A

5%

22
Q

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

A

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

23
Q

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

A
  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)
24
Q

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

A

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

25
Q

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

A

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

26
Q

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

A

cortical thymic epithelial cells

27
Q

___% of cells fail selection in the cortex.

A

95-98%

28
Q

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

A
  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
29
Q

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

A

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

30
Q

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

A

Medullary thymic epithelial cells (mTECs)

31
Q

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

A

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

32
Q

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

A

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

33
Q

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

A

Ensures self-tolerance

34
Q

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.

A

Foxo1

35
Q

What genes are upregulated by Foxo1 ?

A
  • Sphingosine-1-phosphate receptor
  • IL-7R
  • CCR7
36
Q

Sphingosine-1-phosphate receptor (S1PR)

A

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

37
Q

IL-7R

A

gives survival signals to mature T cells (cytokine)

38
Q

CCR7

A

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

39
Q

What are RTEs?

A

RTEs= recent thymic emigrants

40
Q

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

A

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

41
Q

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

A

about 3 weeks

42
Q

How do Treg cells inhibit adaptive immune responses?

A
  1. Deplete the local area of stimulating cytokines
  2. Produce inhibiting cytokines
  3. Inhibit APC activity (inhibit their maturation)
  4. Directly kill T cells
43
Q

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

A

FoxP3

44
Q

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

A

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

45
Q

What is “anergy”?

A

high-affinity interactions without costimulatory ligands

Immunology (17 decks)

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