Week 3 Flashcards

1
Q

Major cytokines produced by Th17 cell types

A

IL-17 and IL-22. (Also IL-21)

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2
Q

IL-17 and IL-22 have many overlapping functions. Wherein do the two cytokines functionally differ?

A

IL-17 is mostly a pro-inflammatory cytokine that orchestrates protection against infections by enhancing the epithelial release of antimicrobial peptides, granulopoiesis, and neutrophil accumulation in peripheral tissues, IL-22 is a homeostatic cytokine preserving the integrity of boundary organs and tissues, and only occasionally exerts a proinflammatory role.

IL-17 can be positioned to be more pro-inflammatory and as a strong inducer of innate immunity, while IL-22 acts in a more regenerative manner at epithelial cell sites

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3
Q

In what form is IL-17 (IL-17A) secreted?

A

Either as a homodimer or as a heterodimer with IL-17F.

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4
Q

What types of cells have been shown to secrete IL-17?

A

Th17 lymphocytes, γ T cells, iNKT cells, and group 3 ILCs, as well as neutrophils and mast cells in the context of inflammation.

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5
Q

What transcription factor is associated with the production of IL-17?

A

RORγt

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6
Q

Why cytokines drive T cells towards a Th17 phenotype?

A

TGF-β, IL-6 and IL-1

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7
Q

What are the two functionally distinct ‘flavors’ of Th17 cells, and what cytokines do they additionally produce?

A

“pathogenic Th17” that secrete IFNγ, and “non-pathogenic Th17” that secrete IL-10.

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8
Q

Which cytokine contributes to the maintenance and expansion (but not initial differentiation) of Th17 cells?

A

IL-23

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9
Q

To what cytokine family does IL-22 belong?

A

IL-10 family

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10
Q

What types of cells produce IL-22?

A

several types of CD4+ and CD8+ T lymphocytes, as well as natural killer T cells, γδ T lymphocytes and type 3 ILCs [21]. In mice, IL-22 release is preferentially associated with Th17 differen- tiation; however, in humans only a limited number of Th17 cells co-release IL-22 with IL-17

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11
Q

What receptor is required for the production of IL-22?

A

ligand-dependent transcription factor aryl hydrocarbon receptor (AHR)

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12
Q

What are the ligands for ligand-dependent transcription factor aryl hydrocarbon receptor (AHR)?

A

both environmental toxins, such as halogenated aromatic hydrocarbons, as well as endogenous ligands, such as breakdown products of aromatic amino acids

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13
Q

What is the receptor for IL-17 in humans and what cells express it?

A

the receptor complex of IL-17, which includes IL-17RA and IL-1s7RC, is widely expressed on epithelial, mesenchymal, and hematopoietic cells

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14
Q

What is the receptor for IL-22 in humans and where is it expressed?

A

In contrast, IL-22 binds to a heterodimer formed by the IL-10 receptor b (IL-10Rb) and the IL-22 receptor (IL-22R); In humans, IL-10Rb is widely expressed, while IL-22R expression is mostly limited to epithelial cells of the skin, lung, and gut including hep- atocytes, and kidney

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15
Q

What soluble factor may contribute to IL-22 availability?

A

A soluble form of the IL-22R1 subunit, named IL-22BP

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16
Q

What can be inferred from the cellular distribution of receptors for IL-17 and IL-22?

A

it can be inferred that while IL- 17 modulates many cells, including cells of adaptive and innate immunity, IL-22 acts specifically on epithelial cells

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17
Q

What intracellular signaling does IL-17/IL-17R ligation lead to?

A

IL-17 to its receptor leads to recruitment of the adaptor protein Act1, which interacts with the scaffold proteins TRAF6 and TAK1 to activate NF-κB and p38/MAPKs

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18
Q

What intracellular signaling does IL-22/IL-22R ligation lead to?

A

IL-22 binding its receptor complex IL-10R2 and IL-22R1 induces phosphorylation of the tyrosine kinases Jak1 and Tyk2, which activate the transcription factor STAT-3 and, to a lesser extent, the MAPKs pathway

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19
Q

What are the main defensive functions of IL-17 signaling?

A

Epithelial cell release of CXCL8 and CXCL1 (neutrophil chemoattractants), G(M)-CSF (neutrophil survival factor), CCL20 (Th17 recruitment), and antimicrobial peptides such as b-defensin-2, mucins, and S100 proteins.

When synergized with type 1 cytokines (TNFa), upregulation of ICAM-1 and MHC class II.

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20
Q

What cell type does IL-17 and IL-22 primarily act upon?

A

Epithelial cells of mucosal barriers

21
Q

What are the tissue regenerative functions of IL-17/IL-22?

A

enhancement of mucosal barrier repair and maintenance by stimulating epithelial cell proliferation and tight junction protein production

22
Q

Which cytokine can be considered to be an ‘upstream’ cytokine of IL-17 and IL-22?

A

IL-23, released by DCs in response to TLR4 signaling.

23
Q

Which transcription factors do LTi development dependent on, and which cytokine is essential for their survival?

A

RORγt and Id2 mediate development; IL-7 mediates survival.

24
Q

What is the role of LTi-like cells in enteric bacteria infection?

A

CD4+ LTi-like cells are an early source of IL-22 production in response to Citrobacter rodentium infection in mice, promoting barrier integrity and protective immunity (Sonnenberg et al, 2010)

25
Q

How are LNs and PPs seeded in the fetus?

A

Fetal LTi induce lymph node and Peyer’s patch development during gestation by activating lymphoid tissue organizer cells at primordial lymphoid organs with lymphotoxin (LT)-α1β2

26
Q

What are the non-effector functions of LTi cells?

A

In addition to seeding lymphoid organs such as LNs and PPs in the fetus, LTi-like cells are required for the post- natal development of cryptopatches, small lymphoid aggregates in the intestine that have the potential to mature into isolated lymphoid follicles (ILF) in response to signals from microbes

27
Q

What transcription factor is required for ILC1 development, and what main cytokine do they produce?

A

ILC1s require the transcription factor T-BET and produce interferon-g

28
Q

What transcription factor is required for ILC2 development, and what main cytokine do they produce?

A

ILC2s express the transcrip- tion factor GATA3 and produce the type 2 cytokines interleukin 5 (IL-5) and IL-13.

29
Q

What transcription factor is required for ILC3 development, and what main cytokine do they produce?

A

ILC3s are dependent on the transcription fac- tor RAR-related orphan receptor gamma t (RORgt) and have the ability to produce IL-17 and/or IL-22

30
Q

What are the two main populations of ILC3s and their associated functions?

A

CCR6- ILC3s coexpressing RORgt and T-BET are mainly found scattered throughout the lamina propria

CCR6+NKp46 fetal lymphoid tissue inducer (LTi) and adult LTi-like cells expressing c-KIT (also known as CD117) seed the gut during fetal develop- ment, develop along a pathway distinct from that of other ILCs, and promote lymphoid tissue development, residing in SILTs.

31
Q

What is SILT?

A

Solitary Intestinal Lymphoid Tissue (SILT) is comprised of cryptopatches and isolated lymphoid follicles (ILFs)

32
Q

What is the cellular composition of a cryptopatch?

A

Cryptopatches are clusters of LTi-like ILC3s surrounded by DCs within a network of stromal cells.

33
Q

What is the difference in the cellular composition of cryptopatches and ILFs?

A

Both contain ILC3s and DCs. ILFs additionally include abundant B cell populations. ILFs are thought to arise from CPs.

34
Q

Do LTi-like ILC3s migrate?

A

Yes, they appear to migrate from the intestine to the MLN in a CCR7-dependent fashion, where they are the main type of ILC.

35
Q

CCR6

A

Chemokine receptor for CCL20. CCR6 is expressed on DCs, B cells and T cells in the GALT. CCL20 is expressed by the FAE.

36
Q

CXCR5 (in the gut/SILT)

A

CXCR5, through its interaction with CXCL13 ligand, induces formation of SILT (cryptopatches and ILFs), and is responsible for recruitment of B cells to these structures, as well as PPs. Mice lacking CXCR5 do not form SILT or PPs.

37
Q

CD122

A

Shared Beta chain of IL2R and IL-15R, expressed on early NK cell progenitors.

38
Q

KIRs

A

NK cell. inhibitory receptors (Killer cell Ig-like receptors) expressed by human NK cells, analogous to the Ly49 receptors in mice.

39
Q

Transciption factors important for NK cell development

A

ID-2, E4BP4

40
Q

Which cytokine is responsible for NK cell homeostasis and survival

A

IL-15, also important for CD8+ T cell homeostasis and survival, likely through signaling through the common chain.

41
Q

Markers of four stage developmental schema of NK cells

A

CD11b-low CD27-low ->
CD11b-low CD27-high ->
CD11b-high CD27-high ->
CD11b-high CD27-low

42
Q

NK receptors for MHC I molecules

A

KIR (human)
Ly49 receptors (mouse)
CD94/NKG2 complexes (both)

43
Q

What are the two main populations of NK cells in humans and their locations/functions?

A

CD56-bright NK cells reside mostly in LOs, have low expression of KIR, and are poorly cytolytic, although expand vigorously in response to DC signaling.

CD56-dim NK cells are found in the peripheral blood, have high expression of KIR and are display goods cytotoxicity.

44
Q

What are the two main populations of NK cells in mice and their locations/functions?

A

CD11b-low NK cells reside in BM, LOs and liver and have high homeostatic proliferation.

CD11b-high NK cells are present in periphery, express high levels of Ly49 receptors, and potent effector functions. Consist of two subpopulations based on CD27 expression.

45
Q

What are the two subpopulations of CD11b-high NK cells in mice?

A

CD11b-high CD27 low NK cells express highest levels of Ly49 receptors and CX3CR1/S1P5

CD11b-high CD27-high NK cells have highest effector cell functions and respond to CXCR3/4 in vitro

46
Q

CD335

A

NKp46 - marker for mouse NK cells.

47
Q

CD161

A

NK1.1

48
Q

CD127

A

IL-7R