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Molecular Mechanisms > Thymus and T cell development > Flashcards

Thymus and T cell development Flashcards

1
Q

what is the thymus? where is it located?

A

Primary lymphoid organ:
- where T cell development and selection occurs
- two lobes
- Thymus in superior mediastinum, in front of great vessels of the heart
- Can study human thymus tissue when it is removed during heart surgery

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2
Q

where do T cells come from to enter the thymus?

A

HSCs in BM are self-renewing
- mature and differentiate to common lymphoid precursor
- T cell precursor leaves BM, enters blood circulation and extravasates into thymus

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3
Q

why is the thymus specialised for T cell development?

A

Thymus must have a specialised environment promote T cell precursor development – cell fate commitment to switch of B cell programs and turn on T cell transcriptional programs

Thymus is instructive – controls T cell maturation, commitment and selection
- Positive selection of functional T cells
- Negative selection of autoreactive T cells

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4
Q

what are the 3 possible outcomes of TCR gene rearrangment?

A
  1. generate TCR that is non-functional
  2. Functional TCR which is protective against pathogens and tumours – positive selection
  3. Functional TCR which is autoreactive and binds strongly to self antigens – negative selection
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5
Q

how are T cells spatially separated in thymic development?

A

During development, T cells are restricted to different thymic microenvironments before full maturation
- cortex for positive selection
- medulla for negative selection

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6
Q

what tissues make up the thymus?

A

2 microanatomical compartments:
- cortex
- medulla

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7
Q

what occurs in the cortex?

A

Where specification of T cells occur – enforces T cell fate
- Positive selection of T cells with functional TCR that recognises MHC+peptide
- Mediated by ctec (cortical thymic epithelial cells)

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8
Q

what occurs in the medulla?

A

Medullary thymic epithelial cells drive central tolerance by 2 processes:
- Process of negative selection – deletion of autoreactive T cells
- Coordinates enforcement of CD4 T cells into Tregs which express FoxP3

Mtecs are fundamental for this – avoids autoimmunity

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9
Q

why is T cell development so controlled?

A

All T cell dev is reliant upon tightly ordered steps – checkpoints they must have to pass through to progress

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10
Q

what markers define T cell development stages?

A

defined by expression of CD4 and CD8

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11
Q

what are the early steps in the process of T cell development (up to positive selection)?

A
  • T cell precursors entering thymus via blood vessels at junction between cortex and medulla are double negative (DN)
  • In thymus, they rearrange beta chain TCR - beta selection - if successful, becomes DP thymocyte
  • then alpha chain rearranged to join beta-chain
  • if initial alpha change rearrangment is non productive - get a second change with second allele
  • test the TCR ability to recognise MHC and peptide in ctecs
  • they get 3-4 days in cortex to generate functional TCR - death by neglect if non-functional
  • If they have functional TCR, they get survival signal
  • Class of MHC they recognise determines if they express CD4 or CD8 - becomes SP thymocyte
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12
Q

what are the latter stages of T cell development (negative selection)?

A

Only following positive selection do T cells migrate from cortical microenvironment into medulla
- At the medulla, they begin negative selection and Treg dev
- Cells are in thymic medulla for 5 days – short duration to screen autoreactivity and Treg function
- Leave thymus after this into the peripheral circulation

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13
Q

what do thymic epithelial cells express?

A

Foxn1 - transcription factor
(also expressed in skin cells but functionally different)

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14
Q

what are the target genes of Foxn1 in TECs?

A

CCL25

DLL4 - delta-like ligand 4

KIT ligand

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15
Q

what does CCL25 induce via Foxn1?

A

Upregulates CCL25 on thymic epithelial cells which activates chemokine receptor called CCR9 on haematopoetic precursor cell
- Recruit common lymphoid progenitors from blood to thymus
- Also CCL21 with CCR7

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16
Q

What does DLL4 induce via Foxn1?

A

Upregulates DLL4 (Delta-like ligand 4 - Notch family) – ligand which is expressed on surface of cortical thymic epithelial cells
- binds to notch 1 on lymphoid precursor
- Notch 1 binding makes precursor commit to T cell lineage
- K/O of DLL4 or notch 1 means T cell development is stunted, and thymus is full of B cells
- B cells are default pathway, so DLL4 suppresses this

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17
Q

what does KIT ligand induce via Foxn1?

A

Upregulates KIT ligand which drives T cell expansion
- Expand T cell precursors to form lots or T cells to deal with selection
- sufficient cells to undergo development and be exported to the periphery

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18
Q

what controls Foxn1?

A

Wnt upregulates Foxn1, as well as BMP and hedgehog (Shh)

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19
Q

what are the main transcriptional regulators of T cell tolerance?

A

Transcriptional regulators AIRE and FEZF2 - expressed by mTECs
- these enable thymic cells control T cell tolerance – screen for autoreactivity

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20
Q

what is AIRE?

A

Autoimmune regulator - not TF, a transcriptional regulator
- enables dysregulated gene expression in mTECs
- allows unique mTECs to express genes that are associated with peripheral tissues e.g. insulin proteins, MBP of CNS
- this peripheral proteins are expressed by mTECs in thymus via AIRE

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21
Q

how does AIRE enable central tolerance?

A

Screen T cells for autoreactive potential by exposing them to body tissues in the thymus before they can cause autoimmunity
- represent peripheral tissues in thymus and delete autoreactive T cells before they ever enter periphery and cause damage

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22
Q

how does AIRE enable peripheral mimecry?

A
  • mTECs become mimetic cells of peripheral cells - acquire TFs of parietal cells and express their genes
  • mosaic of peripheral-self in the medulla

this is only a theory or model!

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23
Q

what happens to T cells which recognise AIRE induced self-proteins?

A

Any T cell with TCR that is self-reactive is deleted
- strong affinity to self leads to apoptosis of autoreactive T cells

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24
Q

what happens if AIRE is not expressed?

A

Lacking/mutations in AIRE means that self-peripheral proteins aren’t presented, autoreactive T cells aren’t deleted, so T cells will leave thymus and attack self-tissues – autoimmunity

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25
Q

when is AIRE function most important?

A

If AIRE expression is restricted to first days after life, and then deleted in mice, the mice are still healthy – window of AIRE function early in life which lasts

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26
Q

is AIRE the only regulator of central tolerance?

A

there are other factors which control this process e.g. FEZF2
- this doesn’t overlap with AIRE, FEZF2 presents its own peripheral proteins

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27
Q

how does TCR affinity affect central tolerance?

A
  • TCR binding with strong affinity to self-proteins above the threshold for activation result in that T cell being deleted
  • low affinity binding can lead to anergy
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28
Q

how is AIRE expression distributed?

A

AIRE is highly heterogenous – different AIRE in different mtecs express different proteins at different times

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29
Q

how can central tolerance be more efficient in the thymus?

A

Dendritic cells in medulla can rip self proteins from mtecs and present them to T cells – more efficient presentation
- DCs from peripheral tissues can pick up self proteins, enter thymus and contribute to tolerance in that way too
- but could DCs present pathogenic proteins to thymic T cells and induce tolerance to these?

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30
Q

how does the size of the thymus affect function? why is this important?

A

The bigger it is, the more TECs, the more selection, the more diversity of T cell repertoire, more protective against pathogens
- Attrition of T cells in infection means we can lose peripheral T cell clones
- Continued thymic activity is crucial to replace T cells that we lose and maintain peripheral diversity
- large thymus avoids clonal restriction

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31
Q

how does thymic size correlate with T cell production?

A

Large thymus – lots of T cell diversity – more protection

Small thymus – reduced capacity to produce T cells, restricted diversity – less immune protection - immunosusceptible
- thymus isn’ t constant throughout life - so atrophy limits T cell immunity

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32
Q

what controls numbers of TECs and therefore thymic size?

A

During thymic dev, thymic epithelial cells express FGFR2iiib receptor
- This is ligated by FGF7, a soluble signalling protein (also called KGF)
- FGF10 binds the same receptor too, but FGF7 is most important

binding of FGF7 to FGFR2iiib drives thymic epithelial proliferation - mitogenic signal

K/O of FGF7 or FGFR23B receptor, mouse has small thymus – less T cell diversity

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33
Q

is thymic activity constant throughout life?

A

No - reduction in thymic microenvironment is common

34
Q

why does the thymus lose size and function?

A

Inherited loss/primary genetic defects: deficiency in Foxn1 in patients – non-functional thymic epithelium, immunodeficiency for T cells - hypoplastic thymus

Acquired acute loss: infection can drive thymic atrophy, pregnancy, irradiation exposure reduces thymus size

Progressive loss: increasing age leads to decline in immune function – age-associated thymic atrophy
- loss of functional TECs and loss of T cell production as we age

35
Q

Can we manipulate thymus to correct atrophy of thymic microenvironment?

A

different approaches:
- expand/stimulate residual thymic epithelial stem cells - regrow thymus
- if thymus is absent - replace thymus with transplant of thymic tissue
- or use stem cell technology - reprogramme stem cells to generate thymic tissue and transplant into patients
- or take BM stromal cells, manipulate to express notch ligands and induce T cell development, but does lack tolerance

aims to increase T cell development

36
Q

why do the cortex and medulla functions need to be balanced when restoring thymic function?

A

Enough protective immunity via cortex – positive selection
Enough tolerance via medulla – negative selection to prevent autoimmunity

Need balance of both – may restore thymic tissue but could cause autoimmunity

37
Q

what evidence is there for the importance of Foxn1?

A

Mutations in Foxn1 in nude mice: lack of thymic epithelium to support development, so T cell deficient – not protected from infection
- has B cells, but not T cells

WT has large thymus and normal T cell dev and export – protected

38
Q

what is Di George Syndrome?

A

Small, hypoplastic thymus, or aplasia (absent thymus)
- Susceptible to opportunistic infection - immunocompromised
- Micro-deletion on chromosome 22.
- spectrum of developmental defects of heart, palate, parathyroid (low calcium levels.
- Defect in Tbx1
- Recurrent infection susceptibility (pneumonia, oral candiasis (yeast).

39
Q

how can Di George Syndrome patients be treated?

A

Take paediatric thymus from patients undergoing heart surgery:
- Slice tissue into in vitro culture
- Transplant donor thymus tissues into quadricep of patient - graft into circulation
- This allows limited T cell recovery
- Some MHC matching issues and some autoimmunity

Balance of treatment – no thymus and no T cells at all or some autoimmunity with enough T cells

40
Q

what is the driving cause of thymic atrophy?

A

chronic loss due to increasing age

acute loss via pregnancy or infection

41
Q

can the thymus regenerate?

A

Thymus has intrinsic capacity to regenerate to return to original size, or even bigger
- Then over time it declines with ageing

If we can understand endogenous regeneration, we could enhance thymus activity in patients

42
Q

what causes chronic age-associated thymic atrophy?

A

Older thymus: replacement of functional thymic tissue with fibrous, adipose tissue
- Driven by sex steroids in puberty
- gradual loss of functional thymic epithelium
- Corresponds to reduced T cell output: restriction of T cell diversity, dominance of memory T cell clones but susceptible to newly encountered pathogens – reduced capacity to respond to new vaccines

43
Q

what is acute thymic loss?

A
  • loss of thymic tissue due to pregnancy/infection
  • but thymic rebound after where it can recover to original size - some degree of regeneration - what controls this?
  • but then gradually declines due to age
44
Q

is the thymus energetically favourable?

A

no - only 5% T cells developing in thymus enter the periphery
- highly wasteful
- hence atrophy once we reach reproductive age

45
Q

what controls thymic recovery following acute loss?

A

cytokines IL-23 and IL-22

46
Q

how does the thymus respond to acute loss?

A
  • expose mouse to irradiation to cause acute thymic atrophy
  • there is loss/apoptosis of DP thymocytes
  • apoptosis is sensed by dendritic cells, which release IL-23
47
Q

how does cytokine IL-23 regulate thymic recovery?

A

IL-23 from DCs triggers innate lymphoid cell type 3 (ILC3s) by binding to its IL-23 receptor on its surface
- ILC3s release IL-22
- IL-22 triggers thymic epithelial cell proliferation and recovery by binding to IL-22 receptor

48
Q

how has IL-22 been shown to enhance thymic recovery?

A

irradiate mice
treat with IL-22
this recovers the thymus

49
Q

how can T cells be recovered for cancer patients?

A

Radiotherapy and chemotherapy treatments - irradiaton and loss of HSCs
- Donor bone marrow HSCs to replace and reconstitute blood and immune system

50
Q

what is the problem with bone marrow transplant for T cell recovery?

A

T cell lineage is slow to recover post transplantation
- some HSCs become lymphoid precursor, enter thymus, selection, commitment, screening etc – long process
- Window of high infectious susceptibility – increased risk of mortality after BM transplant

51
Q

how is bone marrow transplant limited in an elderly person?

A

they have also undergone thymic atrophy, so thymic epithelial function will be limited to generate new diverse T cell repertoire
- Time lag of cells getting to thymus, addition to less efficient thymus so less T cell selection
- Heightened susceptibility to infection because of restricted TCR diversity in aged people

BMT less effective in older people compared to younger

52
Q

how can bone marrow transplants in elderly patients be improved?

A

Give injection of antibody to stimulate lymphotoxin-beta receptor which is expressed on thymic stromal cells
- this enhances rate of T cell recovery - aids precursor entry and development in thymus
- T cells are exported from thymus quicker
- Improve T cell recovery in older indivudals with BMT faster

53
Q

how can thymic epithelial cells be manipulated to enhance T cell recovery?

A

Give FGF7 to expand thymus in mouse models undergoing BMT:
- drove epithelial proliferation and improved recovery
- Less effective in human clinical trials

Give IL-22 to stimulate thymus recovery from ILC3s
- In clinical trials

Sex steroid ablation – onset of puberty drives thymic atrophy
- Block these steroids can enhance T cell reconstitution and reverse atrophy

54
Q

what should be considered when manipulating the thymus?

A

If we want to manipulate thymus tissue in vivo, there must be responsive target cells

absence of thymus/primary deficiencies may require cell/tissue replacement therapy
- generate TECs from stem cells/iPSCs
- do TEC stem cells already exist? what signals regulate them?

55
Q

what are the two thymic epithelial stem cell models?

A

dual epithelial progenitor pool:
- one for cortex, one for medulla

or

single epithelial progenitor pool that has potential to give rise to both cTECs and mTECs

56
Q

how can we identify the stem cell pool of cTECs and mTECs?

A

Approach: take one stem cell and get it to differentiate into all its fates
- Can it differentiate into just cortex, just medulla or both

cell fate mapping

57
Q

what is the approach of cell fate mapping to identify thymic epithelial precursors?

A

Isolate early embryonic thymus from YFP mouse:
- Mouse embryo at day 12 in gestation – can see pouch regions where thymus rudiment forms – immature thymic epithelium which is not differentiated
- Dissect thymus from embryo
- Isolate thymus from mouse with YFP in all cells of body
- Digest thymus with enzyme into single cell suspension – analyse with flow cytometry for YFP and epithelial cell adhesion molecule expression
- In box = epithelial cells expressing YFP

58
Q

how can the isolated YFP-positive thymic epithelium be tested for cell fate?

A

Take a single YFP-epithelial cell and test its developmental potential

Use microinjection into blastocyst:
- Holding needle that keeps WT day 12 embryonic thymus (no YFP expression) in place via suction
- needle injects a single thymic epithelial cell tagged with YFP – back into a microenvironment that provides the normal signals for its development

59
Q

how is the injected YFP thymus kept in vivo?

A

Leave tissue long enough for single cell to undergo dev
- Put in vivo environment where it is vascularised so that dev is sufficient
- Signals from T cells control epithelial maturation
- Inject thymus into system for T cell recruitment to control thymus development
- Transplant thymus under kidney capsule of adult WT mouse – not very invasive and kidney function is normal
- Transplanted thymus is plumbed in due to high vascularisation of kidney – recruits lymphoid precursors, supports T cell dev, exports into periphery
- Can leave thymus to develop and see what happens to the single YFP epithelial cell

60
Q

what did they find when a single YFP thymic epithelial precursor was injected into an embryonic thymus?

A

Single YFP thymic cell gives rise to both cortical and medullary epithelial cells
- It is a bipotent epithelial stem cell
- Single SC population that gives rise to cortical and medullary epithelia

61
Q

what other evidence is there for bipotent thymic epithelial precursors?

A

This group approached it with a different model:
- Took foxn1 deficient animal engineered to have rare but spontaneous foxn1 activation in thymic epithelial cells
- When foxn1 is switched on in a single cell, the single cell gives rise to regions of cortex and medulla
- In both studies, cells from single bipotent progenitor can support positive and negative selection and development of T cells

62
Q

what gives rise to cTECs and mTECs?

A

single epithelial pool with bipotent potential

63
Q

what are the surface markers that can define bipotent epithelial markers?

A

One group found TECs which express MTS24, these included cells with bipotent potential

Then found that cells which didn’t express MTS24 also had bipotent potential

Currently haven’t actually identified a marker

is useful to know as it would allow isolation to generate thymic tissue and perform transplants

64
Q

what is a cTEC specific marker?

A

beta5-t - only expressed in cTECs

65
Q

how can cTEC lineage tracing be done using a mouse model?

A

Cre based K/O:
- mouse 1: Expressed Cre-recombinase under control of beta5t promoter of cTECs
- mouse 2: loxp sites either side of stop codon, with GFP downstream
- when mice are crossed, cre excises stop codon, so GFP is expressed when beta5t is present

GFP expression maintained in cells having expressed beta5t at any point

66
Q

what did the lineage tracing beta5t model find out about mTEC lineage?

A

GFP expression seen in CTECs and MTECs
- Indicates that MTECs must have passed through a stage where at some point the beta5t promoter was active
- mTECs passed through stage of having hallmark cTEC expression

mTECs arise from cells bearing cortical-associated molecules

67
Q

how does beta5t expression change during bipotent progenitor maturation?

A

Bipotent progenitor which is beta5t negative
- Beta5t is switched on in the TEC precursor, expressing hallmarks of CTECs such as CD205, IL-7
- These give rise to true CTECs which express b5t
- others give rise to MTECs which switched off b5t

68
Q

are mTECs maintained by the cTEC lineage?

A

Inducible cre model, control cre switch on via deoxycyclin
- Inject mice with deoxcylcin to switch on cre in b5t-expressing cells
- in mice less than 1 week old: CTECs and MTECs are green – still passing through b5t-expressing stage
- If injection with deoxycylin is done beyond one week old to switch on beta5t, there is only labelling of CTECs and not MTECs

shows that adult mTECs are maintained independently of cTEC couple of weeks post birth
- Switch in where MTECs are coming from or how they’re maintained in different stages of life

69
Q

how is the medulla maintained in embryo and early stages?

A

medulla maintained by beta5t positive bipotent TEC progenitor forming beta5t-positive precursor which can become beta5t-positive cTEC or beta5t-negative mTEC

70
Q

how is the medulla maintained in juvenille/adult stages?

A

medulla maintained by beta5t negative medullary epithelial progenitor fraction
- but how?

71
Q

what sustains the medulla in the post-natal period?

A

Take mice with mutation in NIK (kinase part of NF-KB pathway)
- These mice have small medulla, no AIRE-positive MTECs – lack of tolerance – multi-organ autoimmunity

Identified small population of MTECs that express claudin 3 and 4 (adhesion proteins)
- Injected claudin3/4-positive MTECs into thymus of mouse with NIK mutation
- This injection recovered MTEC+ AIRE cells and sustained medulla lifelong and maintained tolerance

Claudin3/4-positive cells are an mTEC-associated postnatal progenitor which maintains medulla at later life stages

72
Q

what happens when claudin-positive mTEC precursors are put in clonal cultures?

A

Lots of active stem cells in embryonic stages
reduces in activity in newborn,
activity of cells fully drops in later stages e.g. 8 weeks old – linked to thymic atrophy

73
Q

what happens to claudin3/4 mTEC progenitors in RAG2-/- mice?

A

Mouse deficient for RAG2 (no TCR rearrangement – no double positive or single positive thymocytes)
- there is no drop off in stem cell activity, it is maintained

74
Q

why do claudin3/4 mTEC progenitors drop off in activity over time?

A

Single positive T cells may inhibitory feedback to MTEC SCs, leading to their reduced activity:
- Symbiotic relationship where T cells can control MTECs and vice versa
- the more T cells that are developed may use up the mTECs

No thymopoiesis = mTECSC activity maintained
Active thymopoiesis = mTECSC activity inhibition

75
Q

what stem-cell based strategies could be used to generate functional thymic epithelium? what are the pros and cons?

A
  1. isolate bipotent TEC precursors
    - can’t do this yet as no markers identified
  2. use of embryonic stem cells
    - reprogramme to make functional TEC
    - ethical issues
    - genetic compatibility issues - tolerance
    - inefficient
  3. use of iPSCs and somatic reprogramming
    - take mature TEC and revert to precursor
    - still quests of tolerance and efficiency
76
Q

how could iPSCs be studied and used to regenerate TEC?

A
  • in a nude mouse that lacks a thymus via foxn1 deficiency

Blastocyst injection:
- Blastocyst from foxn1 deficient mouse
- Take IPSCs that have capacity to express foxn1
- Use microinjection to inject IPSCs into nude blastocyst
- Transfer to pseudopregnant mouse – implantation and normal development

Chimeric animal is formed
- iPSC nude chimera forms a large, functional thymus with organised medulla and cortex microenvironments with normal T cell development

77
Q

why are iPSCs limited in TEC regeneration?

A

could induce teratomas or malignancies
- need to make sure TEC fate is induced

78
Q

how can somatic reprogramming be studied to renew TECs?

A

mouse with foxn1 expression under tamoxifen control
- Injection of mouse with tamoxifen causes all cells switch on foxn1

Isolate fibroblasts from mouse (Mouse embryonic fibroblasts) – mesodermal lineage
- Treat MEF with tamoxifen to switch on foxn1

If foxn1 is switched on, can we reprogram cells to diverge from fibroblast to become a TEC to support T cell development

79
Q

can reprogrammed fibroblasts form TECs?

A

With foxn1 switched on in fibroblast:
- reprogrammed cells look epithelial
- reprogrammed cells upregulate cytokeratins which are intermediate filaments of epithelial cells – epithelial phenotype
- switching on foxn1 can switching germ layer identity from mesoderm to ecto/endoderm

80
Q

can reprogrammed fibroblasts form functional thymic epithelium?

A

Take reprogrammed cells and inject into kidney capsule of host mouse to be plumbed into vasculature:
- This reprogrammed graft had DP and SP thymocytes
- In periphery of mouse, SP T cells were present

From reprogramming fibroblasts with foxn1, they turned into TECs with cellular machinery to support T cell development and export into periphery

81
Q

what are the limitations/remaining questions of reprogrammed fibroblasts for TEC recovery?

A

tolerance? Are the mTECs providing self-antigens, are Tregs produced?
Are there effective tumour responses ?
is there long-term stability?
can dendritic cells enter?

Molecular Mechanisms (8 decks)

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