Week 3 Flashcards
Major cytokines produced by Th17 cell types
IL-17 and IL-22. (Also IL-21)
IL-17 and IL-22 have many overlapping functions. Wherein do the two cytokines functionally differ?
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
In what form is IL-17 (IL-17A) secreted?
Either as a homodimer or as a heterodimer with IL-17F.
What types of cells have been shown to secrete IL-17?
Th17 lymphocytes, γ T cells, iNKT cells, and group 3 ILCs, as well as neutrophils and mast cells in the context of inflammation.
What transcription factor is associated with the production of IL-17?
RORγt
Why cytokines drive T cells towards a Th17 phenotype?
TGF-β, IL-6 and IL-1
What are the two functionally distinct ‘flavors’ of Th17 cells, and what cytokines do they additionally produce?
“pathogenic Th17” that secrete IFNγ, and “non-pathogenic Th17” that secrete IL-10.
Which cytokine contributes to the maintenance and expansion (but not initial differentiation) of Th17 cells?
IL-23
To what cytokine family does IL-22 belong?
IL-10 family
What types of cells produce IL-22?
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
What receptor is required for the production of IL-22?
ligand-dependent transcription factor aryl hydrocarbon receptor (AHR)
What are the ligands for ligand-dependent transcription factor aryl hydrocarbon receptor (AHR)?
both environmental toxins, such as halogenated aromatic hydrocarbons, as well as endogenous ligands, such as breakdown products of aromatic amino acids
What is the receptor for IL-17 in humans and what cells express it?
the receptor complex of IL-17, which includes IL-17RA and IL-1s7RC, is widely expressed on epithelial, mesenchymal, and hematopoietic cells
What is the receptor for IL-22 in humans and where is it expressed?
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
What soluble factor may contribute to IL-22 availability?
A soluble form of the IL-22R1 subunit, named IL-22BP
What can be inferred from the cellular distribution of receptors for IL-17 and IL-22?
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
What intracellular signaling does IL-17/IL-17R ligation lead to?
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
What intracellular signaling does IL-22/IL-22R ligation lead to?
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
What are the main defensive functions of IL-17 signaling?
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.
What cell type does IL-17 and IL-22 primarily act upon?
Epithelial cells of mucosal barriers
What are the tissue regenerative functions of IL-17/IL-22?
enhancement of mucosal barrier repair and maintenance by stimulating epithelial cell proliferation and tight junction protein production
Which cytokine can be considered to be an ‘upstream’ cytokine of IL-17 and IL-22?
IL-23, released by DCs in response to TLR4 signaling.
Which transcription factors do LTi development dependent on, and which cytokine is essential for their survival?
RORγt and Id2 mediate development; IL-7 mediates survival.
What is the role of LTi-like cells in enteric bacteria infection?
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)
