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AI - Innate Lymphoid Cells > Identification of ILCs > Flashcards

Identification of ILCs Flashcards

1
Q

Where do ILCs develop?

A

In the bone marrow.

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2
Q

Give the order of ILC development.

A

CLP -> ChILP -> ILC subtypes.

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3
Q

Which ILCs are similar to NK cells?

A

ILC1s.

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4
Q

Does E4bp4 drive ILC production?

A

Yes - it acts upon the common lymphoid progenitor.

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5
Q

What are LTi cells?

A

LTi = Lymphoid Tissue Inducing Cells

  • > precursors of the cells that form the lymph nodes
  • > part of the ILC family.
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6
Q

Give the general roles of the cytokines produced by ILCs.

A

Roles in inflammation, wound healing and fat metabolism.

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7
Q

Give 3 defining characteristics of ILCs.

A
  1. No Rag-dependent antigen receptors.
  2. No myeloid cell markers.
  3. Have lymphoid morphology.
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8
Q

Give the TF that drives ILC1 production.

A

T-bet

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9
Q

Give the cytokines that stimulate production of ILC1s.

A

IL-12, IL-15, IL-18 - released by epithelial cells in response to intracellular microbes, viruses and tumours.

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10
Q

Give the cytokine produced by ILC1s upon activation.

A

IFNy.

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11
Q

Give the main difference between NK cells and ILC1s.

A

ILC1s are not cytotoxic.

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12
Q

How are NK cells distinguished from ILC1s?

A

Eomes expression is more critical than T-bet in NK cells.

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13
Q

Give roles of ILC1s.

A

Macrophage activation and production of ROS.

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14
Q

Give the TF that drives ILC2 production.

A

GATA3/RORa

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15
Q

Give the cytokines that stimulate production of ILC2s.

A

IL-25, IL-33 and TSLP - released by epithelial cells in response to large parasites, tissue injury and during allergic responses.

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16
Q

Give cytokines produced by ILC2s.

A

IL-4, IL-5 and IL-13 (type 2)

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17
Q

Which ILC population produces amphiregulin?

A

ILC2s - involved in repair.

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18
Q

Give the roles of ILC2s.

A

Mucus production, M2 macrophage activation, tissue repair, vasodilation and thermoregulation.

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19
Q

Give the role of ILC2s in asthma.

A
  • induce polarisation of naive CD4+ T cells to produce Th2 cells.
  • produce IL-5 which induces eosinophila in the lungs
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20
Q

Give the TF that drives ILC3 production.

A

RORyt

21
Q

Give the cytokines that stimulate production of ILC3s.

A

IL-1b and IL-23 - released in the response to extracellular microbes, including fungi.

22
Q

Give the cytokines produced by ILC3s.

A
  • IL-17 and/or IL-22.
  • sometimes produce IFNy or IL-13.
  • produce GM-CSF.
23
Q

Give the roles of ILC3s.

A

Stimulating phagocytosis, and production of anti-microbial peptides.

24
Q

How were ILC2s first identified?

A

As IL-13 producing nuocytes - innate response to helminth infection.

25
Q

Give evidence for the roles of nuocytes during helminth infection.

A
  • IL-13-eGFP mice have higher IL-13 production when given IL-25 and IL-33 to induce a Th2 response. GFP+ cells seen in the lamina propria.
  • Nuocytes account for why Rag -/- mice can still give a Th2 response, without T cells.
26
Q

Give the cell surface markers of nuocytes.

A

eGFP+ T1/ST2+ IL-17BR+

27
Q

Describe the experiments done with the helminth infection model to further characterise nuocytes.

A
  • IL-1rl -/- (no response to IL-33) mice could not clear helminth infection until day 14.
  • IL-17BR -/- (no response to IL-25) mice could not clear helminth infection until day 20.
  • Double KOs could not clear infection.
  • Infection caused increased nuocyte production in the MLN.
  • When these nuocytes are cultured, IL-7 and IL-33 drive their expansion.
  • Adoptive transfer of these expanded nuocytes into IL-17BR -/- mice restores the IL-25 driven Th2 response.
28
Q

Discuss evidence for the importance of IL-25 for nuocyte activity.

A
  • IL-25 does not further increase nuocyte expansion in culture with IL-7 and IL-33.
  • But, addition of IL-25 to IL-17BR -/- mice that have had adoptive transfer of expanded nuocytes does further increase the goblet cell hyperplasia that occurs upon nuocyte transfer.
29
Q

What is IL-17BR?

A

A subunit of the IL-25 receptor.

30
Q

What is C-Kit a marker of?

A

Cells in the early stages of development - not normally expressed by mature lymphocytes.

31
Q

What is CD45 a marker of?

A

Haematopoietic cells.

32
Q

What cell population were known to be present in cryptopatches?

A

Lin- C-Kit+ population of lymphocytes,

33
Q

What did the presence of C-Kit indicate about the lymphocytes in the cryptopatches?

A

That this was a novel cell population, different from lymphocytes already characterised - as these cells expressed C-Kit but were not in the early stages of development.

34
Q

Describe the characterisation of ILC3s.

A
  • NKp46+ CD3- cells identified in the spleen and lamina propria of mice.
  • Staining for NKp46 and RORyt showed coexpression of these in this cell population.
  • Population of NKp46+ RORyt+ cells identified in mice expressing GFP under the control of RORyt; these cells were intermediate for NK1.1
  • This population are reduced in the lamina propria of germ-free mice.
  • NKp44+ CD56+ cells from the tonsils were shown to produce IL-22.
  • Stimulation of PPs from mice with IL-23 in vitro resulted in IL-22 production from NKp46+ CD3- cells.
35
Q

Give a description of the cell surface markers characterised on ILC3s.

A

RORyt (hi) NKp46+ NK1.1 (int)

36
Q

Why were the RORyt (hi) NKp46+ NK1.1 (int) cells identified not NK cells?

A
  • Genetic fate mapping showed NK cells never express RORyt.
  • These cells did not kill MHC- YAC1 cells.
  • These cells did not produce IFNy.
37
Q

Should there be expression of lineage defining TFs in progenitor cells.

A

Yes - these must be expressed during the precursor stage, in order to drive the gene expression that drives cells to become a particular subtype.

38
Q

Give a description of the cells identified as a possible ILC progenitor.

A

Lin-Id2+IL7Ra+CD25-α4β7+

39
Q

What other markers are expressed by Lin-Id2+IL7Ra+CD25-α4β7+ cells?

A

C-Kit and CD244

40
Q

What is CD244?

A

an NK cell receptor for NKG2D ligands, that is probably involved in intracellular signalling.

41
Q

What is PZLF?

A

TF involved in myeloid differentiation, upregulated in ILC development. Implicated in promyelocytic leukaemia.

42
Q

What happens when Lin-Id2+IL7Ra+CD25-α4β7+ cells are adoptively transferred into nude mice?

A

Reconstitution of the helper ILC network; GATA3+ ILC2s; RORγt+ ILC3s (CCR6-); CCR6+ RORγt+ CD4+ LTis – in the lamina propria of the intestine. ILC1s (NK 1.1+NKp46+Eomes-) identified in the liver.

43
Q

What are CHILPs?

A

CHILP = Common Helper Innate Lymphoid Progenitor

  • ILC progenitor, does not give rise to NK cells.
  • Lin-Id2+IL7Ra+CD25-α4β7+
44
Q

What distinguishes NK cells from helper ILCs?

A

Helper ILCs are not cytotoxic, and express IL-7Ra - not expressed by NK cells.

45
Q

Give evidence for the role of E4bp4 in ILC development.

A

In E4bp4 KO mice;

  • universal loss of ILC3s
  • loss of LTi cells
  • loss of ILC precursors
  • increased severity of infection when infected with citrobacter rodentium (causes IBS)
  • loss of ILC2s in the lung
46
Q

At what stage of ILC development is E4bp4 critical?

A

For the CLP -> CHILP transition.

47
Q

Give evidence that Id2 acts downstream of E4bp4 in ILC development.

A

When BM from WT + Id2-GFP mice is injected into E4bp4 KO mice, Id2 rescues the ILC population.

48
Q

What is currently thought about the roles of E4bp4 and Id2 in ILC development?

A

That both Id2 and E4bp4 are required for ILC precursors and lineage commitment - previous CHILP identification had suggested that Id2 was the earliest lineage marker. of ILCs.

AI - Innate Lymphoid Cells (2 decks)

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