Lecture 8: Development of T Lymphocytes Flashcards Preview

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Flashcards in Lecture 8: Development of T Lymphocytes Deck (94)
1

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

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

2

Where is the thymus located?

Superior to the heart, in between the lungs

3

When does the thymus begin to produce T cells?

around 12-13 weeks of gestation

4

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

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

5

The thymus is what kind of organ?

epithelial-lymphoid

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

6

When do HSCs first arrive to the thymus?

week 7-8 of gestation

7

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

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

8

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

FOXN1

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

9

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

lighter; medulla

10

Immature T cells are located in the ___________

cortex

11

What 2 cell types are found in the thymic stroma?

1) fibroblasts
2) epithelial cells

12

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

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

13

From which germ layer do thymic epithelial cells derive?

endoderm

14

What transcription factor is essential for functional maturation of TECs?

Foxn1

15

What is one important function of TECs?

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

16

How do T cells communicate in the thymus?

via Notch/Delta signaling

17

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

Delta-Like 1,4

18

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

kills them when they interact with insulin

19

Where are macrophages and DCs located in the thymus?

cortex and medulla

20

Deletion of autoreactive T cells is accomplished in a process called

negative selection (accomplished by macrophages?)

21

Deletion of autoreactive T cells is accomplished in a process called

negative selection (accomplished by macrophages?)

22

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

CD34 (

23

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

CD4 and CD8 (double positives)

24

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

10% CD4
5% CD8

25

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

5%

26

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

5%

27

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

decreases

28

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

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)

29

What is the hallmark of a pre-T cell?

expression of CD1

30

What is the immature single positive stage of T cells?

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

(precursor for both TCRab and TCRyd T cells)

31

What stage comes after the ISP stage?

double positive (CD4 and CD1a)

32

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

Delta-Like 1, 4

33

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

alpha: double positive stage
y,d,b: Pre-T stage

34

Only T cells with functional ______ chains will survive

beta

35

Only T cells with functional ______ chains will survive

beta

36

What event terminates lineage plasticity in T cell development?

Notch and Delta interaction

37

What are the recombination activation genes in T cell development?

RAG1 and RAG2

38

What are the recombination activation genes in T cell development?

RAG1 and RAG2

39

What is the role of SCID-X1?

causes changes in IL7 which participates in optimizing rearrangement of receptor

40

What percentage of cells in the thymus as yd positive?

2%

41

What does the PreTCR complex consist of?

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

42

What is Beta selection?

selection for functional rearranged TCRbeta

43

What 3 events occur during beta selection?

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

44

What percentage of cells in the thymus as yd positive?

2%

45

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

CD8

double positive cells (CD4 and CD8)

46

When is RAG expression re-expressed?

during the double positive stage when TCRValpha genes are rearranged

47

What are ITAMs?

immuno receptor tyrosine based activation motif

48

True or False: there is allelic exclusion in TCRValpha rearrangement

FALSE

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

49

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

alpha chain

50

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

Their own

51

What are ITAMs?

immuno receptor tyrosine based activation motif

52

What is affected in Bare Lymphocyte Syndrome?

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

53

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

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

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

Their own

55

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

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

56

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

LOW

57

Why is too high affinity negatively selected?

suggestive of self reactive

58

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

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

59

What is positive selection of TCRab T cells?

selection of T cells that recognize antigens presented by MHC molecules

60

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

LOW

61

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

RAG (so that no further rearrangement can take place)

62

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

undergo apoptosis

63

Positive selection skews the selected TCRab repertoire towards _____ _________

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

64

Define negative selection

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

65

Where does negative selection occur predominantly?

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

66

What is AIRE?

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

67

What is the purpose of AIRE?

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

68

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

Insulin

69

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

after they survived both positive and negative selection

70

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

medulla

71

How do mature CD4 and CD8 cells leave the thymus?

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

72

TCRyd T cells develop from _____ cells

ISP

73

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

expression of pTa

74

Do TCRyd express CD4 or CD8?

NEITHER (both neg)

75

Do TCRyd bind MHC Class I or Class II?

NEITHER (binds antigens directly)

76

What are the 2 dominant TCRyd T cells?

1) cells that express d1 with various y genes
2) TCRy9d2 (majority circulating)

77

What are the functions of TCRyd cells?

1) TCRd1: lyse stressed/transformed epithelial cells
2) TCRy9d2: recognize non-peptide phosphor antigens on mycobacterium and malaria parasite

78

AIRE mutations can result in what?

autoimmune polyendocrinopathy candiasis ectodermal dystrophy (APECED)

79

Positive selection is _____ mediated; Negative selection is __________ mediated

MHC; affinity

80

What is CD1?

MHC analogs that can present lipid antigens to TCRyd cells

81

How many CD1 proteins are there in humans?

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

82

What do CD1b, c, and d bind to?

glycolipid antigens

83

NKT cells express which 2 markers?

1) TCRab (T cells)
2) CD56 (NK cells)

84

Which cells develop into NKT cells?

DP thymocytes that recognize CD1d/glycolipids expressed on cortical thymocytes

85

NKT cells express which CD?

CD4

(or have neither CD4 nor CD8)

86

Where are NKT cells located?

liver, spleen, BM, lymph

87

What is the purpose of Tregs?

to suppress autoimmunity

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

88

How were Treg discovered?

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

89

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

FOXP3

90

What percentage of mature CD4 thymocytes are Tregs?

5-10%

10% blood CD4 cells

91

What is the purpose of Tregs?

to suppress autoimmunity

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

92

Can Tregs develop outside of the thymus?

YES

93

What 3 Treg cells develop in the periphery?

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

94

What happens in patients with mutations in Foxp3?

no Tregs