PRRs
Host pattern recognition receptors (PRRs) have been selected to detect pathogen components, such as bacterial lipopolysaccharide (LPS), that possess these features.
What are invariant and essential? (evolutionarily conserved, structural, difficult to mutate due to constraints on function, etc.)
What are the caveats of using cytokines as therapeutics?
It can be a “double edged sword” or cause “cytokine storms”.
How do NK recognize tumor cells that have downregulated MHC I expression?
Ly49 on NK cells is an inhibitory receptor that prevents killing when it binds to MHC. Lack of MHC binding takes away this inhibition so that the NK cells can kill. Bonus: Signaling through ITIMs.
What is the function of the C3 complement component?
Opsonization and enhancing B cells response to antigens
What are the characteristics of HSC?
They are self-renewing and pluripotent.
These membrane-bound PRRs, homologues of a protein required for antifungal defense in Drosophila, detect microbial products in the extracellular space and in endosomes.
What are Toll-like receptors (TLRs)?
While type I IFNs are recognized by many cell types and can thus induce systemic responses, type III IFNs are preferentially recognized and induce responses at these locations.
What are epithelial/barrier surfaces?
How did scientists determine whether ILCs are tissue resident versus circulating cells? What did they find?
Used a parabiosis model in which a CD45.1 mouse and a CD45.2 mouse were surgically connected. They determined that ILCs found in the tissue were host derived.
How are NETs associated in COVID-19 disease progression?
They can cause an immunothrombotic state.
Single cell studies have changed the way we think about hematopoiesis. Describe what we have learned from this data.
Single cell studies have demonstrated more heterogeneity during hematopoiesis. This supports a lineage continuum model rather than a lineage tree model.
What are 3 examples of viral PAMPs?
Possible examples:
Nucleic acids, viral glycoproteins, products of infection, pathology associated with infection
How do JAK inhibitors prevent cytokines signaling?
By preventing STAT translocation to the nucleus
How were cytokine reporter lines used in the discovery of ILCs?
Cytokine reporter lines (eg. IL-13, IL-4) were used to identify which immune cells were the main producers of that cytokine. Scientists observed that the majority of cells producing those cytokines were lineage (CD3/CD19) negative despite microscopically looking like lymphocytes.
List 3 ways by which macrophages can destroy pathogens after phagocytosis.
1. Acidification
2. Toxic oxygen-derived products (superoxide, hydrogen peroxide)
3. Antimicrobial peptides (defensins, cathelicidin)
4. Enzymes (lysozyme, acid hydrolases)
5. Toxic nitric oxides
6. Competitors (Lactoferrin)
Janeway proposed that an adjuvant is required in order to achieve robust B and T cell responses to a novel protein antigen because adjuvants stimulate these two attributes of immune activation.
What are antigen uptake/presentation and costimulatory activity?
Inflammasome assembly leads to activating cleavage of pro-IL-18/pro-IL-1β/etc. by this key enzyme or closely related enzymes.
What is caspase-1? (caspase-11, etc.)
The signaling pathways for type I and type III IFNs are largely shared, but they differ at these key proteins.
What are the initial receptors? (IFNAR1 and IFNAR2 for type I IFNs vs. IFNLR1 and IL-10Rβ for type III IFNs)
What was surprising about the NK response in MHC-I deficient mice? Bonus: provide an explanation for these findings.
NK cells were hyporesponsive instead of exhibiting an autoimmune response.
Bonus: Licensing: NK are subjected to a licensing test. If they don’t pass, they can’t kill. Licensing is the engagement of an inhibitory receptor. Licensed cells can produce IFN-y and unlicensed cells become anergic. Disarming model: Talk to Taku lol
Describe a method to experimentally differentiate the function of tissue resident vs. monocyte-derived macrophages?
Many answers possible. One example from lecture is to identify a monocyte-derived macrophage specific gene (ex. Ms4a3) and use a Cre reporter system to differentiate the role between tissue resident and monocyte-derived macrophage functions
Provide an example of a word or phrase used in class that Chris Hunter dislikes.
REDUNDANCY
How do we deal with endogenous PAMPS/ DAMPS (ex: endogenous retroelements, DNA damage, mitochondrial DNA, foreign looking transcripts)
Limiting amount, limiting recognition, requiring multiple signals
How does Listeria induce IFN-g production in CD4 T cells?
Macrophages produce IL-12 in response to listeria infection, which, when coupled with TCR stimulation, drives the production of IFN-g from CD4+ T cells. When macrophages are in the presence of IFN-g, listeria cannot enter the cytosol of the macrophage which helps it to control infection
Describe how ILCs function in tissues. How do they get activated? How do they signal to other cells? Bonus: provide an example
Local cells serve as sensors and signal to ILCs via activating signals such as cytokines and neuropeptides. ILCs produce cytokines that act on other local cells.
Ex. Tuft cells in the intestine sense helminth infections causing them to release IL-25. IL-25 activates ILC2s in the intestine to produce IL-4, IL-5, and IL-13. These cytokines act on epithelial stem cells causing tuft cell hyperplasia.
What is the spectrum of macrophage activation?
M1 macrophages are classically pro-inflammatory while M2 macrophages are classically anti-inflammatory, however macrophages can fall anywhere along the spectrum.
Describe an assay to detect HSC activity/self renewal?
Serial Transplantation