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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
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

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