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HD Exam 1 > Lecture 10, T Cell Maturation > Flashcards

Lecture 10, T Cell Maturation Flashcards

1
Q

What 4 types of T cells can a HSC (originally from the marrow) develop into in the thymus?

A
  • T helper (CD4)
  • T cytotoxic (CD8)
  • Natural killer T (NKT)
  • T regulatory (Treg)
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2
Q

The epithelial component of the thymus develops from the ________ pharyngeal pouch bilaterally at the ________ week of gestation.

A
  • 3rd

- 4th

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3
Q

Thymic cells begin to migrate during the ________ week of gestation, and they fuse at the midline (superior to the heart) by the ________ week of gestation.
What types of cells fuse?

A
  • 6th
  • 7th
  • HSCs (colonize during 7th-8th week)
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4
Q

The thymus begins to produce T cells during the _______ week of gestation, and mature T cells begin to egress the thymus at the end of the _______ week of gestation.

A
  • 12th-13th

- 13th

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5
Q

What 2 mutations provided evidence that the thymus is an organ of thymopoeisis?

A
  1. Large deletion that causes DeGeorge Syndrome (AKA velo-cardial-facial syndrome- VCFS)
  2. Nonsense mutation in FOXN1 gene
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6
Q

What are the effects of DeGeorge Syndrome?

How could you surgically treat it?

A
  • Hypoparathyroidism, heart defects, athymia: T cells are rarely detectable
  • Thymus implants give rise to higher T cell number and restore immune response
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7
Q

What are the effects of a FOXN1 gene mutation?

A

FOXN1 can’t work as a TS factor

- No hair (affects keratinization), no thymus (*requires keratin 5 for thymic medulla and keratin 8 for thymic cortex)

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8
Q

What 2 cell types make up the thymic stroma?

A
  • Fibroblasts (capsule, septa w/bv’s)

- Epithelial cells (cortical, medually, Hassall’s bodies)

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9
Q

Besides fibroblasts and epithelial cells, what other 3 major cell types are present in the thymus?

A
  • DCs
  • Macrophages
  • HSCs (and T cells are different stages)
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10
Q

Are thymic epithelial cells developed from endo, meso, or ectoderm?

A

Endoderm

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11
Q

*What TS factor is essential for the development of thymic epithelial cells (TECs)?

A

FOXN1

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12
Q

*What important ligand do thymic epithelial cells express?

What does this ligand bind?

A
  • Delta-like 1, 4

- Notch receptor

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13
Q

What MHC do thymic epithelial cells express?

A

I (HLA A, B, C) and II (HLA DR)

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14
Q

Why are developing T cells interacting w/thymic epithelial cells?

A

TECs are expressing peripheral tissue ag, such as insulin (testing for selection)

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15
Q

In which parts of the thymus would you find DCs/macrophages?

Where are they concentrated?

A
  • Cortex and medulla

- Concentrated in cortico-medullary junction

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16
Q

*What are the 2 primary functions of macrophages/DCs in the thymus?

A
  • Ag presentation and phagocytosis of apoptotic thymocytes

- Deletion of autoreactive T cells: negative selection

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17
Q

About what % of T cells in the thymus are double positive (DP)?
CD4+ only?
CD8+ only?
Double negative (DN)?

A

~ 80%
~ 10%
~ 5%
~ 5%

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18
Q

Name the 4 major events of T cell development (just read).

A
  1. T lineage commitment: restricted of lineage choices
  2. Proliferation: Expansion of committed cells
  3. Differentiation: gaining of new surface markers (helps us track and ID cells)
  4. Maturation: selection and gaining of immune functions
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19
Q

*Describe the CD markers on a HSC that will eventually become a mature T cell (step 1).
What receptor does it express that binds Delta-like 1,4 ligand of TEC?

A

CD34+, CD1a-, CD7-
- Notch

(at this point can still become B cells, monocytes, DCs)

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20
Q

*What cell does the HSC become on its way to becoming a mature T cell (step 2)?
What CD markers does it express?

A
  • T/NK cell

CD34+ (starts declining), CD1a-, CD7+

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21
Q

*What cell does the T/NK cell become on its way to becoming a mature T cell (step 3)?
What CD markers does it express?

A
  • Pre-T cell

CD34 (low/neg), CD1a+

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22
Q

*What cell does the pre-T cell become on its way to becoming a mature T cell (step 4)?
What CD markers does it express?

A
  • ISP (immature single-positive T cell)

CD34-, CD1a+, CD4+, CD3 (low)

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23
Q

*What cell does the ISP become on its way to becoming a mature T cell (step 5)?
What CD markers does it express?

A
  • Double positive T cell

CD1a+, CD4+, CD8+

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24
Q

*What cell does the DP T cell become on its way to becoming a mature T cell (step 6)?
What CD markers does it express?

A
  • Single positive T cell

CD1a-, CD4 or 8+

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25
Q

At which stage in T cell development is the T cell committed to T cell lineage?

A

Pre-T cell (started *via Notch binding delta-like 1,4 of TEC during HSC stage)
- Becomes CD1a+

26
Q

At which stage in T cell development does positive and negative selection occur?

A

DP T cell (rearrangement of TCRalpha)

27
Q

What gene rearranges during the pre T cell stage?

A

Beta (via RAG)

- Also gamma, delta

28
Q

During which stage is the surrogate alpha chain created (pTalpha)?
What does pTalpha combine with?

A
  • Immature single positive (ISP) T cell
  • Combination of the rearranged TCRbeta chain w/ pTalpha forms the pre-TCR.

(generally thought that this skews T cells to alpha-beta vs. gamma-delta)

29
Q

MHC expressed by ____________________ dictates down modulation of either the CD4 or CD8 co-receptors.

A

Thymic cortical epithelial cells

30
Q

What is the defect in Bare Lymphocyte Syndrome (BLS)?

What types of cells are affected?

A

Defect in MHC II expression; the development of CD4+ T cells is affected

31
Q

Explain the general basis of negative selection.
What stage of T cell does it?
*What cell(s) induce it?

A

When TCR on a DP cell binds antigen/MHC with high affinity, it is signaled to undergo apoptosis.
- Induced by DCs/macrophages, + TECs as well.

32
Q

GAD67, Insulin, and IA-2 are e.g.’s of genes that are induced by the TS factor known as AIRE, found in what type of thymic cells?

A

Medullay TECs. (not found in DCs…)

- Used to negatively select T cells (w/high affinity for these specific organ ag’s)

33
Q

A mutation in AIRE would lead to what dz?

Major sx?

A

Autoimmune Polyendocrinopathy Candiasis Ectodermal Dystrophy (APECED).
- Fungal infections to tongue, toes

34
Q

Positive selection occurs in the thymic ________, negative selection occurs in the thymic ________.

A
  • Cortex

- Medulla

35
Q

Where do HEVs enter the thymus?

A

Cortico-medullay junction

- T cell progenitors go from medulla, out to cortex, then back to medulla and can leave if successful

36
Q

Which stage in T cell development is the Precursor for both TCRalpha/beta and TCRgamma-delta T cells?
- What dictates lineage choice?

A

Immature single-positive (ISPs)
- Successful beta selection

(This process selects cells with productive and functional rearranged TCR-beta genes signaling via the preTCR. Cells that do not form a functional preTCR die by apoptosis. Cells that survive the beta-selection step proliferate and expand. This enormous expansion of cells at this stage is responsible for generating the large number of thymocytes with TCR-alpha/beta in the thymus.)

37
Q

Are the CD4 and CD8 positive or negative in gamma-delta T cells?

A

Usually both CD4- and CD8-

38
Q

What markers do natural killer T cells (NKTs) express?

A

Both markers for T cells (TCRalpha-beta) and NK cells (CD56+)
- Either CD4+ or CD4- + CD8-

39
Q

*What 2 TS factors are essential for the development of Tregs?

A

TSLP and FOXP3 (NOT FOXN1 of thymic dz)

40
Q

Why would we care about Th3 cells?

A

Oral tolerance induction

- E.g. allergies to peanuts

41
Q

A mutation in FOXP3 would cause someone to not have any Tregs. What condition would this lead to?

A

Immune dysregulation, polyendocrinopathy, and X-linked inheritance (IPEX)

42
Q

What types of cells are found in Hassall’s bodies (of the thymus)?

A

Concentric organization of epithelial cells.

43
Q

Of which T cell stage does expression of RAG genes first occur for rearrangement of TCR beta (+ delta, gamma) chain?

A

Pre-T cell (CD34-/low, CD1a+)

44
Q

Of which T cell stage does expression of RAG genes occur for rearrangement of TCR alpha chain?

A

DP T cell (CD4+, CD8+, CD1a+)

45
Q

Of which T cell stage does expression of precursor for both TCRalpha-beta and TCR-gamma-delta T cells occur, as well as the expression of preT-alpha and preTCR-beta selection?

A

ISP T cell (CD34-, CD1a+, CD4+, CD3low)

46
Q

Of which T cell stage does positive and negative selection occur?

A

DP T cell (CD4+, CD8+, CD1a+)

47
Q

During TCR gene rearrangement, what causes deletion of the TCR delta locus?
During what stage does this occur?

A

RAG expression is re-expressed and rearrangement of TCRV𝛂 genes are initiated. The rearrangement of V𝛂 causes deletion of TCRδ locus
- DP stage

48
Q

Explain allelic exclusion w/r/t TCRV-alpha.

A

There is no allelic exclusion in TCRV𝛂 rearrangement. It is possible that there are two different rearranged V𝛂 chains, each is associated with a common Vβ. Subsequent positive selection will ensure that each T cell only has a single functional specificity, although two different 𝛂 chains are expressed

49
Q

DP CD4+CD8+ thymocytes that recognize CD1d/glycolipids expressed on cortical thymocytes develop into _________ cells.

A

NKT

50
Q

Where are NK T cells typically found?

A

Liver, spleen, BM and lymph nodes

51
Q

What surface marker presence indicates an HSC has become an NK/T cell?

A

CD7+

52
Q

What surface marker presence indicates an HSC has become an ISP cell?

A

CD4+

express preT-alpha, which induces some expression of CD3, to join and form the pre-TCR

53
Q

How are CD1 proteins similar to MHC?

A

Distantly related to MHC molecules, however they lack polymorphism.

54
Q

What are some of the names of the 2 types of gamma-delta T cells?
Which predominates?

A
  • TCRδ1

- TCRγ9δ2 (80% of circulating gamma-delta T cells)

55
Q

What are the main functions of TCRδ1 gamma-delta T cells?

A
  • TCRδ1: Cytotoxic activity, recognized stressed cells and lipid Ag; lyse stressed-epithelial cells
56
Q

What are the main functions of TCRγ9δ2 gamma-delta T cells?

Also, what important cytokine to they produce?

A
  • TCRγ9δ2: Anti-microbial immuno-surveillance; recognize intracellular bacteria (also extracellular- TB); phosphor antigens. Immune regulation.
  • Produce IFN-gamma that affects cytotoxicity of NK and NKT cells and the generation of Th1 cells.
57
Q

NKT cells develop in the thymus from the CD4() CD8() thymocytes.

A

CD4+ and CD8+

58
Q

Mature NKTs egress the thymus and populate the ________, _________, ________, and ________.

A

Liver, spleen, BM, and lymph nodes.
(0.02- 0.2% of the peripheral blood
T cell compartment)

59
Q

Discuss the general pattern of cytokine release from NKTs.

A

Rapidly produce both Th1 (IFN-gamma) and Th2 cytokines (IL-4, IL-5, IL-10) upon
triggering. Thus, they play a role in immunoregulation.

60
Q

*Mice subjected to thymectomy between day 2 and 4 post natal develop organ-specific
autoimmune dz’s. The autoimmune dz’s can be prevented by infusion of syngeneic T cells obtained from adult thymus or spleen. What discovery did this lead to?
What is this phenomenon referred to as?

A

It was concluded that the thymus generate suppressor cells with specificity for autoreactive T cells that may escape negative selection during the development of T cells. This mode of suppression of autoreactivity is referred to as dominant tolerance.

61
Q

These “suppressor cells” turned out to be Tregs, which are positive for what 2 major CD markers?

A

CD4+, CD25+

62
Q 
*During T cell devo:
What CD becomes present as an HSC?
NK/T cell?
Pre-T cell?
ISP T cell?
A

34,
7,
1a,
4

HD Exam 1 (15 decks)

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