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)
How are LNs and PPs seeded in the fetus?
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
What are the non-effector functions of LTi cells?
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
What transcription factor is required for ILC1 development, and what main cytokine do they produce?
ILC1s require the transcription factor T-BET and produce interferon-g
What transcription factor is required for ILC2 development, and what main cytokine do they produce?
ILC2s express the transcrip- tion factor GATA3 and produce the type 2 cytokines interleukin 5 (IL-5) and IL-13.
What transcription factor is required for ILC3 development, and what main cytokine do they produce?
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
What are the two main populations of ILC3s and their associated functions?
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.
What is SILT?
Solitary Intestinal Lymphoid Tissue (SILT) is comprised of cryptopatches and isolated lymphoid follicles (ILFs)
What is the cellular composition of a cryptopatch?
Cryptopatches are clusters of LTi-like ILC3s surrounded by DCs within a network of stromal cells.
What is the difference in the cellular composition of cryptopatches and ILFs?
Both contain ILC3s and DCs. ILFs additionally include abundant B cell populations. ILFs are thought to arise from CPs.
Do LTi-like ILC3s migrate?
Yes, they appear to migrate from the intestine to the MLN in a CCR7-dependent fashion, where they are the main type of ILC.
CCR6
Chemokine receptor for CCL20. CCR6 is expressed on DCs, B cells and T cells in the GALT. CCL20 is expressed by the FAE.
CXCR5 (in the gut/SILT)
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.
CD122
Shared Beta chain of IL2R and IL-15R, expressed on early NK cell progenitors.
KIRs
NK cell. inhibitory receptors (Killer cell Ig-like receptors) expressed by human NK cells, analogous to the Ly49 receptors in mice.
Transciption factors important for NK cell development
ID-2, E4BP4
Which cytokine is responsible for NK cell homeostasis and survival
IL-15, also important for CD8+ T cell homeostasis and survival, likely through signaling through the common chain.
Markers of four stage developmental schema of NK cells
CD11b-low CD27-low ->
CD11b-low CD27-high ->
CD11b-high CD27-high ->
CD11b-high CD27-low
NK receptors for MHC I molecules
KIR (human)
Ly49 receptors (mouse)
CD94/NKG2 complexes (both)
What are the two main populations of NK cells in humans and their locations/functions?
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.
What are the two main populations of NK cells in mice and their locations/functions?
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.
What are the two subpopulations of CD11b-high NK cells in mice?
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
CD335
NKp46 - marker for mouse NK cells.
CD161
NK1.1
CD127
IL-7R
