Week 5 Flashcards
TF of Plasmacells
IRF4, Blimp-1
TF of Bmems
Bach2
What chemokine receptor do B cells use to cycle between LZ and DZ?
CXCR4
Contents of Light Zone of GC
FDCs (appearing light because so much projections from fDC), LZ B cells, Tfh cells
Contents of DZ
Rapidly proliferating B cells
Cell surface markers used to differentiate between LZ and DZ B cells
CD83 and CD86 - high on light zone, low on dark zone
What is the mechanosensor that is responsible for MaDCAM-1 polarization on HEV cells?
Piezo1
How long do tissue-derived macrophages last?
self-renew permanently, tend to not be proliferative. Will renew from local precursors.
What are the four ways that macrophages phagocytose?
complement, antibody, antibody-complement, and apoptotic cells
what processes are efferocytosis critical for?
development, regeneration, apoptotic cell clearance
What are human NK markers?
CD3- CD56+
What are mouse NK markers?
CD3-NK1.1+
Is thymus required for NK cel development?
No
From which common progenitor do NK cells develop?
NK cell/T cell progenitor
What are the lymphocyte percentages of NK cells in the peripheral blood, spleen and liver?
5-20% in peripheral blood
~5% in spleen, abundant in liver
Over 70% in decidual tissue!
What are main roles of NK cells?
Cell-mediated killing (ADCC)
early IFNg production
How do NK cells kill?
predominantly perforin and granzymes, but can also use TNFa, Fas ligand and TRAIL
Which cytokine is required for NK cell development and survival throughout lifespan?
IL-15
Which cytokine augments NK cell cytolytic activity and survival during activation?
Interferon a/B (Type 1)
Which cytokines induce IFNg production in NK cells and are required for their proliferation?
IL-12 and IL-18
Which cytokine induces proliferation, increases cytotoxicity, and is used to grow NK cells in vitro?
IL-2
What types of infections are NK-deficient individuals susceptible to?
viral infections, particularly herpesvirus.
May also be more susceptible to cancers.
What is the “missing self” hypothesis?
NK cells will target cells (tumor cells or infected cells) that are not displaying MHC class I
Why is there such variety in NK cell ‘phenotypes’ in any individual?
NK cells express a variety of activating and inhibitory receptors, which can pair with various adaptors (CD3, ITAMs, etc.) Very promiscuous pairing.
What transcription factors are important for development of NK cells?
Id2, Nfil3 (E4BP4)
What is the process of ‘licensing’ for NK cells?
Through MHC I. They must learn to be inhibited when they see MHC I. Then they can go into the periphery. Similar to positive and negative selection in T cell development. Some become anergic, and these may help to fight viruses and tumors.
What are the two activating factors for NK cells of a virus-infected cell?
Sensing of a viral component on the cell membrane by an NK cell activating receptor.
NK2GD / NK2GD ligand (kill-me flags) interaction - ‘stress signals’ in target cell
What is an example of an NK cell directly recognizing a virus particle on an infected cell?
Ly49H+ NK cells can recognize MCMV-derived m157 through the Ly49H protein (signaling through DAP12)
What are the activating and inhibitory intracellular signalers in NK cells?
(mouse) Ly49A, C, G, I … have ITIM motfis (recruit phosphatases, inhibit responses) - almost always ligate MHC I
(mouse) Ly49D, H, L, P … have ITAM motifs (through adaptors like DAP12; recruit Sky and ZAP-70; Activate.
In humans, KIR genes have replaced Ly49 genes; also have activating and inhibitory flavors. inhibitory mostly recognize MHC I
What is NKG2D?
NK sensor for cellular “stress”
C-type lectin-like
homodimer expressed on all NK cells and some CD8 T cells
Signals through DAP10
conserved between mouse and human
What are NK2GD ligands?
Markers of cellular stress Look like MHC class I, but do not require B2m nor need a peptide for stability
induced in infected or tumorous cells. low levels on healthy cells.
What is NK2GD ligand shedding?
Thought to be shed by tumor cells, but might be shed by myeloid cells surrounding tumors. Also known as MICA and MICB in humans.
What are some cancer therapies using NK cells?
Prevention of NKG2D shedding by antibody that can also activate NK cells through Fc portion
Antibodies that block inhibitory markers on tumor cells.
What is EAE?
Experimental Autoimmune (Myelo)encephalitis
Why was studying EAE important for the discovery of Th17?
It was found that IL-23 receptor removal was important in protecting against EAE, i.e. IL-23 leads to disease. This led to the discovery of Th17.
What was one of the first evidence of ILC?
Cellular sources of IL-22 in Rag-/- mice that protected against Citrobacter rodentium.
Sonnenberg found that these cells were CD3- (not T cells), NK1.1-, (not NK cells),
CD127+ (IL7R), c-kit+, CD90+ RORgt+
What markers are ILC negative for?
CD3, CD5, CD19, B220, Ly6G, SiglecF, CD11b, CD11c
Why were ILCs originally confused with NK cells?
Some ILCs have NK cell receptors, however, they are independent from IL-15
What do Rag2-/-il2rb-/- mice lack
All T and B cells, plus no NK cells
What do Rag2-/-il2rg (common chain)-/- mice lack?
All T and B, plus no NK cells and no ILCs
What does the IL-2 common gamma chain recognize?
IL-2, IL-4, IL-7, IL-9, IL-15
What do Rorc-/- mice lack
No RORgt cells
Do all RORgt-dependent ILC3s express T-bet?
No. There are some that also express T-bet alongside RORgt.
What are the two (or three) distinct populations of iLC3s in the intestine?
Both share CD90 and CD127.
T-bet+ (NKp46) has lower CCR6 has more IL-12R. May be more inflammatory. These cells seem to arise later in development
T-bet- has higher CCR6
There also may be an inflammatory ILC3 that is circulatory, that is positive for both T-bet, CCR6, and negative for CD4 and NKp46. Shown to enter CNS during inflammation
What are the differences between the two distinct ILC3 populations?
T-Bet+CCR6- ILC3s seem to arise later in development (after weaning) and do not appear in germ-free mice.
CCR6+ ILC3s seem to be present before weaning and without microbial stimuli (LTi cells)
What are CCR6+ ILC3s?
LTi cells and LTi-like cells. Require RORgt. Heterogenous in CD4 expression. Initiate lymph organ development with LTo through LTaB.
How does fate mapping work?
You can cre/flox a reporter gene that will be permanently removed if the cre-ed gene is ever expressed.
How to ID ILC1 in the gut?
T-bet+NK1.1+NKp46+ cells that are negative for Eomesodermin and fate map negative for RORgt
What are the shared cell markers of ILCs?
CD25 (IL2Ra), CD127 (IL-7R), CD90 (Thy.1)
NK cells are an exception.
What do ILCs require for development?
Development independent of Rag1/2 or thymus, but require the IL-7R and the common-gamma chain
Also require Id2 for development and progenitors in the BM (and liver for LTi cells)
What is an example of the adaptive immune system controling ILCs?
At weaning, there is a massive STAT3 activation in the epithelial cells of mice that is thought to be downstream of IL-22 signaling. This is resolved by 9 weeks. However, this resolution is not apparent at 9 weeks in Rag-/- mice, indicating that they have continued IL-22 signaling without an adaptive immune arm.
What are some ways that the adaptive immune system can affect ILCs?
Competition for pro-survival cytokines
control of the microbiota
Tregs might lower IL-23
IL-10 production.
