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MIMM 314 > Lecture 11 - Defects in T Cell Development > Flashcards

Lecture 11 - Defects in T Cell Development Flashcards

1
Q

describe the development of the thymus and its stroma (3 stages)

and the TFs involved in each step

A
  1. thymus organogenesis - TBX1
  2. TEC development - FOXN1
  3. TEC function - AIRE
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2
Q

Describe development of TECs

A

underdeveloped cells migrate to pericardium from the pharynx and develop into TECs btwn 1st and 2nd trimester in humans

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3
Q

what causes DiGeorge Syndrome?

A

deletion in long arm of chromosome 22

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4
Q

2 types of DiGeorge Syndrome

A
  1. INCOMPLETE
  2. COMPLETE
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5
Q

3 symptoms of incomplete DiGeorge Syndrome

A
  1. variable thymic size
  2. increased susceptibility to infections
  3. immunodysregulation leading to autoimmunity
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6
Q

2 symptoms of complete DiGeorge Syndrome

A
  1. no thymus
  2. SCID –> T cell deficiency
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7
Q

why do people have variable symptoms in DiGeorge Syndrome

A

diff genes are lost

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8
Q

genes lost in DiGeorge Syndrome

A

diff genes but ALWAYS TBX1

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9
Q

role of TBX1

A

essential early on for pharyngeal segmentation of the thymus (embryonic day 9 in mouse)

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10
Q

what happens if Tbx1 expression is lost before embryonic day 9?

A

no thymus –> required to establish thymic tissue

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11
Q

what happens if Tbx1 expression is lost after embryonic day 9?

A

thymus is normal, therefore gene is dispensible after day 9

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12
Q

2 treatments of DiGeorge Syndrome

A
  1. transfer mature T cells
  2. thymus transplant
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13
Q

describe the transfer of mature T cells for DiGeorge Syndrome

A

mature T cells from donor are injected into patient but they won’t get full TCR repertoire

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14
Q

describe thymus transfer for DiGeorge Syndrome

A

not full thymus –> use thymic splices that have been depleted of hematopoietic cells so only epithelial cells remain

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15
Q

what type of immunodeficiency occurs with FOXN1 deficiency?

A

Nude SCID

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16
Q

what is FOXN1?

A

TF expressed by epithelial cells in skin and thymus

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17
Q

role of FOXN1 in thymus

A

necessary for thymic organogenesis –> allows differentiation of cTECs and mTECs from progenitors

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18
Q

what does FOXN1 deficiency cause?

A

no thymic epithelial cells –> no thymus –> no T cells

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19
Q

treatment for FOXN1 deficiency?

A

thymus transplant

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20
Q

what does APECED stand for?

A

Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy

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21
Q

another name for APECED?

A

Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1)

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22
Q

what causes APECED/APS-1?

A

Aire deficieny

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23
Q

what does Aire stand for?

A

autoimmune regulator

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24
Q

do all patients with APECED have the same phenotypes?

A

No

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25
Q

why do patients with APECED have different phenotypes?

A

Aire-deficiency can mean there’s full dysfunction or alter levels of certain genes/pathways –> diff tissues are targeted

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26
Q

6 possible symptoms of APECED

A
  1. vitiligo
  2. alopecia
  3. hypoparathyroidism
  4. ovarian/testicular failure
  5. type 1 diabetes (uncommon)
  6. chronic candida infection
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27
Q

2 types of treatment for APECED

A
  1. symptom management
  2. immunosuppression
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28
Q

what cells become autoreactive in APECED?

A

T cells and B cells

29
Q

how do autoreactive B cells contribute to diversity of phenotypes in APECED?

A

autoreactive B cells make auto-antibodies that target IFN and IL which can block the IFN and IL responses

30
Q

what is the result of RAG deficiencies?

A

B and T cell deficiency

31
Q

what type of mutations give similar phenotypes to RAG deficiency?

A

mutations in genes involved in recombination of receptor gene segments

32
Q

2 therapies for RAG deficiency

A
  1. hematopoeitic stem cell transplant
  2. gene correction/gene editing
33
Q

how does gene correction/editing work?

A

fix mutations which corrects gene expression in patient’s progenitor cells and re-implant

34
Q

what type of therapy is NOT effective in RAG deficiency?

A

thymic transplant

35
Q

why is thymic transplant not effective for RAG deficiency?

A

RAG deficiency directly impacts hematopoietic cells, not thymic tissue

36
Q

3 causes of X-linked SCID

A
  1. common gamma chain deficiency
  2. IL-7Ra deficiency
  3. JAK3 deficiency
37
Q

what do common gamma chain, IL7Ra, and JAK3 deficiencies lead to?

A

impaired cytokine signaling –> T cell deficiency

38
Q

2 therapies for X-linked SCID

A
  1. hematopoeitic stem cell transplant
  2. gene correction/editing
39
Q

why can we use hematopoeitic stem cell transplant for X-linked SCID?

A

because we can give cells with the proper cytokine receptors and signaling molecules so they can make mature T cells

40
Q

what does thymic atrophy lead to?

A

loss of thymocytes and/or destruction of thymus –> leads to decreased naive T cells and reduces TCR diversity

41
Q

what are causes of thymic atrophy?

A
  1. aging
  2. changes in sex hormones
  3. inflammatin
  4. infection
  5. stress
  6. cytoablative therapies
42
Q

4 results of age-related thymic atrophy

A
  1. decrease in TECs
  2. loss of definitive cortical-medullary junctions
  3. increase in perivascular space
  4. increase in adipose tissue
43
Q

what is an indirect way to determine thymic function?

A

look at egress of naive T cells from thymus

44
Q

describe looking at naive T cells in circulation to determine thymic function

A

expect to see them going into circulation to meet new Ag throughout lifetime

if there is reduced number of naive T cells in circulation, indicates poor thymic function

45
Q

what is a more direct way of looking at thymic function?

A

detecting the amount of TCR excision circle harbouring signal joint (TREC)

46
Q

What are TRECs?

A

circular episome produced during recombination of TCRalpha chain

47
Q

how can we use TRECs to indicate thymic function?

A

TRECs in T cells normally go away but naive T cells will still have them so we can detect the number of TRECs to indicate the number of naive T cells in circulation

48
Q

how does the number of thymic emigrants change with age?

A

reduced thymic output with age

49
Q

how does the number of thymic emigrants change after thymectomy?

A

reduces even more with age compared to non-thymectomy patients

but still some naive T cells can egress because thymectomy doesn’t remove the whole thymus

50
Q

what type of surgery removes the thymus?

A

heart surgery

51
Q

how does adult thymectomy affect survival?

A

significant reduction in survival with thymectomy

52
Q

what is the main cause of age-related thymic atrophy?

A

thymic stromal cell degeneration, specifically TECs

53
Q

describe the number of thymocytes in young vs old mice who have received fetal thymic graft

why is this significant?

A

old mice maintain thymocytes

therefore, maintaining the structure of the thymic epithelium is necessary for thymocyte

54
Q

what causes thymic atrophy with age and in pregnancy?

A

androgens!

55
Q

what was the early study that showed that androgens induce thymic atrophy?

A

when various animals were castrated, thymus growth persists and atrophy slows down

56
Q

what is an external factor that can impact thymic function?

A

infections

57
Q

2 ways that infection can induce thymic dysfunction

A
  1. pathogen infects thymic cells
  2. immune response produces inflammatory cytokines which increases glucocorticoids that affect thymus size
58
Q

what causes ACUTE thymic atrophy?

A

loss of immature thymocytes (DP and DN) due to inflammation or stress

59
Q

effect on thymocytes with chronic vs acute infection

A

inflammatory cytokines causes reduction in cytokines in chronic and acute cases but acute can recover

60
Q

if acute injuries are affecting progenitors, what can happen when the stimulus stops?

A

get new progenitors from BM that seed the thymus and reconstitute the T cells

61
Q

how does reconstitution of thymus change with age?

A

slower with age

62
Q

why do chemotherapy patients also receive bone marrow transplants?

A

chemotherapy depletes hematopoietic cells and their progenitors –> BM transplant reconstitutes these populations

63
Q

regarding BM transplant, what determines the outcome?

A

time btwn BM transplant and T cells coming out of thymus

64
Q

what happens if there is a large gap btwn when BM is transplanted and T cells exit the thymus? (4)

A

there are fewer T cells, so can lead to:
1. cancer relapse
2. development of secondary malignancies
3. re-activation of latent infection
4. new infections

65
Q

how does the gap btwn BM transplant and T cell regeneration change with age?

A

gap increases with age

66
Q

4 possible treatments for boosting thymus function after acute damage

A
  1. sex steroid inhibitors
  2. IL-7 treatment
  3. soluble factors that help TEC function
  4. recall the beads with notch to make T-lineage committed progenitor cells
67
Q

why can IL7 be used to treat acute thymus damage?

A

stimulates proliferations of progenitor T cells

68
Q
A

MIMM 314 (23 decks)

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