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Host Defense > Lecture 8: Development of T Lymphocytes > Flashcards

Lecture 8: Development of T Lymphocytes Flashcards

1
Q

HSCs home to the thymus and develop into 1 of 4 cells. What are those 4?

A

1) T helper (CD4)
2) Cytotoxic (CD8)
3) Natural Killer T (NKT)
4) T regulatory (Treg)

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2
Q

Where is the thymus located?

A

Superior to the heart, in between the lungs

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3
Q

When does the thymus begin to produce T cells?

A

around 12-13 weeks of gestation

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4
Q

True or False: by the time the baby is born, the peripheral T cell repertoire is established to the point that thymectomy does not cause immediate immune deficiency

A

TRUE (mature T cells can leave the thymus and colonize peripheral lymphoid organs at the end of 13 weeks of gestation)

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5
Q

The thymus is what kind of organ?

A

epithelial-lymphoid

epithelial component develops from 3rd pharyngeal pouch bilaterally at 4 weeks of gestation

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6
Q

When do HSCs first arrive to the thymus?

A

week 7-8 of gestation

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7
Q

What provides the genetic evidence for the thymus as the organ of thymopoiesis?

A

DiGeorge Syndrome or Velo-Cardio-Facial Syndrome (deletion of ch22q11)

Patients exhibit Athymia (undetectable T cells)
Thymus implants give rise to higher T cell numbers

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8
Q

What transcription factor is absolutely essential for T cell maturation/the thymus?

A

FOXN1

mutations in it insert stop codon leading to no hair or no thymus

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9
Q

Mature T cells stain _________ and are located in the thymic _________

A

lighter; medulla

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10
Q

Immature T cells are located in the ___________

A

cortex

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11
Q

What 2 cell types are found in the thymic stroma?

A

1) fibroblasts

2) epithelial cells

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12
Q

What cell types are found in the lymphoid compartment of the thymus?

A

HSCS, thymocytes, mature T cells, natural killer T cells, Tregs

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13
Q

From which germ layer do thymic epithelial cells derive?

A

endoderm

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14
Q

What transcription factor is essential for functional maturation of TECs?

A

Foxn1

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15
Q

What is one important function of TECs?

A

make cytokines required for T cell development (IL7, SCR, IL1, IL6, IL15)

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16
Q

How do T cells communicate in the thymus?

A

via Notch/Delta signaling

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17
Q

What is the cell surface ligand (for Notch receptor) on T cells?

A

Delta-Like 1,4

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18
Q

What effect of does insulin have on T cells of the thymus?

A

kills them when they interact with insulin

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19
Q

Where are macrophages and DCs located in the thymus?

A

cortex and medulla

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20
Q

Deletion of autoreactive T cells is accomplished in a process called

A

negative selection (accomplished by macrophages?)

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21
Q

Deletion of autoreactive T cells is accomplished in a process called

A

negative selection (accomplished by macrophages?)

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22
Q

What is the marker for HSCs in the thymus? How abundant are they?

A

CD34 (

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23
Q

The majority of the cells in the thymus are positive for which cluster differentiations?

A

CD4 and CD8 (double positives)

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24
Q

Of the mature T cells in the thymus, what percent are CD4? CD8?

A

10% CD4

5% CD8

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25
Q

What percentage of T cells are double negative for CD4 and CD8?

A

5%

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26
Q

What percentage of T cells are double negative for CD4 and CD8?

A

5%

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27
Q

As we age, daily production of T cells by thymus __________ (increases/decreases)

A

decreases

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28
Q

What are the 4 important developmental evens in the generation of mature T cells?

A

1) T lineage commitment: once they are in thymus, options are limited to T cell lineage
2) Proliferation: (expansion)
3) Differentiation: (gain new surface markers)
4) Maturation: (selection and gaining of immune functions)

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29
Q

What is the hallmark of a pre-T cell?

A

expression of CD1

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30
Q

What is the immature single positive stage of T cells?

A

When they go from being just CD1+ to CD4+ as well

precursor for both TCRab and TCRyd T cells

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31
Q

What stage comes after the ISP stage?

A

double positive (CD4 and CD1a)

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32
Q

What drives differentiation of double positive cells into CD4 or CD8 cell?

A

Delta-Like 1, 4

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33
Q

Rearrangement of the alpha chain occurs during the ____________ stage while rearrangement of the gamma, delta, beta chains occur during the _____________ stage

A

alpha: double positive stage

y,d,b: Pre-T stage

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34
Q

Only T cells with functional ______ chains will survive

A

beta

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35
Q

Only T cells with functional ______ chains will survive

A

beta

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36
Q

What event terminates lineage plasticity in T cell development?

A

Notch and Delta interaction

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37
Q

What are the recombination activation genes in T cell development?

A

RAG1 and RAG2

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38
Q

What are the recombination activation genes in T cell development?

A

RAG1 and RAG2

39
Q

What is the role of SCID-X1?

A

causes changes in IL7 which participates in optimizing rearrangement of receptor

40
Q

What percentage of cells in the thymus as yd positive?

A

2%

41
Q

What does the PreTCR complex consist of?

A

1) surrogate alpha chain
2) rearranged TCRbeta
3) signal transduction molecules CD3

42
Q

What is Beta selection?

A

selection for functional rearranged TCRbeta

43
Q

What 3 events occur during beta selection?

A

1) termination fo Vbeta rearrangement by degrading RAG proteins
2) induction of rapid proliferation
3) increase CD3 expression

44
Q

What percentage of cells in the thymus as yd positive?

A

2%

45
Q

After beta selection, ISP cells express ____ and develop into _______________.

A

CD8

double positive cells (CD4 and CD8)

46
Q

When is RAG expression re-expressed?

A

during the double positive stage when TCRValpha genes are rearranged

47
Q

What are ITAMs?

A

immuno receptor tyrosine based activation motif

48
Q

True or False: there is allelic exclusion in TCRValpha rearrangement

A

FALSE

there are potentially 2 different rearranged Valpha chains, each associated with common Vb.

49
Q

What is the ONLY chain that does NOT undergo allelic exclusion?

A

alpha chain

50
Q

Will patients who receive BM transplants regenerate T cells that recognize foreign antigens in the context of their own MHC or the donors?

A

Their own

51
Q

What are ITAMs?

A

immuno receptor tyrosine based activation motif

52
Q

What is affected in Bare Lymphocyte Syndrome?

A

development of CD4+ T cells (defect in MHC II expression)

53
Q

What feature of TCR selection is particularly dangerous towards generating auto-reactive T cells?

A

the fact that TCRs are selected on the basis of self MHCs

whole system relies entirely on antigen - use that to screen what is induced and what is not

54
Q

Will patients who receive BM transplants regenerate T cells that recognize foreign antigens in the context of their own MHC or the donors?

A

Their own

55
Q

What is the basis for intrathymic negative selection/central tolerance?

A

apoptosis of DP cells whose TCR binds antigen/MHC with too HIGH of affinity

56
Q

The interaction of TCRab/CD3 complex with self peptides and MHC antigens must be of _____ affinity to be positively selected

A

LOW

57
Q

Why is too high affinity negatively selected?

A

suggestive of self reactive

58
Q

Can epithelial cells mediate negative selection? If so, when is that important?

A

Yes; especially important in patients with BM transplants (because macs and DCs are donor-derived)

59
Q

What is positive selection of TCRab T cells?

A

selection of T cells that recognize antigens presented by MHC molecules

60
Q

The interaction of TCRab/CD3 complex with self peptides and MHC antigens must be of _____ affinity to be positively selected

A

LOW

61
Q

Once DP cells with LOW affinity TCR for self pepties are rescued from apoptosis, they proliferate and shut down the expression of _____

A

RAG (so that no further rearrangement can take place)

62
Q

What happens to cells that express TCRab that do NOT recognize self peptides?

A

undergo apoptosis

63
Q

Positive selection skews the selected TCRab repertoire towards _____ _________

A

self peptides (increasing potential of generating autoreactive T cell clones)

64
Q

Define negative selection

A

deletion of mature T cells that bind strongly to MHC/antigens

65
Q

Where does negative selection occur predominantly?

A

cortical-medullary region (high density of thymic DC cells there)

66
Q

What is AIRE?

A

Auto Immune Regulator Element gene –> encodes transcription factor that induces expression of battery of peripheral tissue antigens by thymic medullary epithelial cells

67
Q

What is the purpose of AIRE?

A

to promote central tolerance of thymocytes by inducing negative selection, contributing to the prevention of organ specific autoimmunity

68
Q

What are some examples of specific genes expressed by mTECs that root out potential self reactive T cells?

A

Insulin

69
Q

When do DP cells commit to single CD4 or CD8 cells?

A

after they survived both positive and negative selection

70
Q

Mature CD4 and CD8 cells are found predominantly in the ________ of the thymus

A

medulla

71
Q

How do mature CD4 and CD8 cells leave the thymus?

A

via blood vessels in the septa of the cortical-medullary junction

72
Q

TCRyd T cells develop from _____ cells

A

ISP

73
Q

What is responsible for skewing the ISP cells towards TCRab lineage?

A

expression of pTa

74
Q

Do TCRyd express CD4 or CD8?

A

NEITHER (both neg)

75
Q

Do TCRyd bind MHC Class I or Class II?

A

NEITHER (binds antigens directly)

76
Q

What are the 2 dominant TCRyd T cells?

A

1) cells that express d1 with various y genes

2) TCRy9d2 (majority circulating)

77
Q

What are the functions of TCRyd cells?

A

1) TCRd1: lyse stressed/transformed epithelial cells

2) TCRy9d2: recognize non-peptide phosphor antigens on mycobacterium and malaria parasite

78
Q

AIRE mutations can result in what?

A

autoimmune polyendocrinopathy candiasis ectodermal dystrophy (APECED)

79
Q

Positive selection is _____ mediated; Negative selection is __________ mediated

A

MHC; affinity

80
Q

What is CD1?

A

MHC analogs that can present lipid antigens to TCRyd cells

81
Q

How many CD1 proteins are there in humans?

A

4 (CD1a, 1b, 1c, and 1d)

82
Q

What do CD1b, c, and d bind to?

A

glycolipid antigens

83
Q

NKT cells express which 2 markers?

A

1) TCRab (T cells)

2) CD56 (NK cells)

84
Q

Which cells develop into NKT cells?

A

DP thymocytes that recognize CD1d/glycolipids expressed on cortical thymocytes

85
Q

NKT cells express which CD?

A

CD4

or have neither CD4 nor CD8

86
Q

Where are NKT cells located?

A

liver, spleen, BM, lymph

87
Q

What is the purpose of Tregs?

A

to suppress autoimmunity

why too high of levels can become dangerous –> will tell body not to kill tumor when it should

88
Q

How were Treg discovered?

A

infusing T cells into athymic mice, (CD4 CD25) which prevented development of organ specific autoimmune diseases

89
Q

expression of which transcription factor in the CD3 CD4 cells is essential for development of Tregs?

A

FOXP3

90
Q

What percentage of mature CD4 thymocytes are Tregs?

A

5-10%

10% blood CD4 cells

91
Q

What is the purpose of Tregs?

A

to suppress autoimmunity

why too high of levels can become dangerous –> will tell body not to kill tumor when it should

92
Q

Can Tregs develop outside of the thymus?

A

YES

93
Q

What 3 Treg cells develop in the periphery?

A

1) TGFb induced Treg from CD4
2) T reg type 1: IL10
3) T helper 3 (Th3): oral tolerance induction

94
Q

What happens in patients with mutations in Foxp3?

A

no Tregs

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