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ACE w1 Flashcards

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1
Q

List IL17 family cytokines. Which is most extensively studied?

A

IL17A - IL17F (six total)

IL17A is most studied; A&F are targeted by biologics

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2
Q

List IL17 receptors

A

IL17RA - IL17RE (five total)

IL17A binds to IL17RA and IL17RC

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3
Q

Which cells can produce IL17?

A

Th17 cells, CD8+ T cells, NK cells, ILCs, mast cells, Paneth cells, etc.

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4
Q

Which upstream cytokines promote IL17 secretion by non-T cells?

A

inflammatory cytokines such as IL1B and IL-23.

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5
Q

What cell markers are expressed by CD4+ Recent thymic emigrants (RTEs?)

A

CD31 (PECAM), although this is not the greatest marker. Better to use expression of complement receptors 1 and 2 (CR1 (CD35) and CR2 (CD21))

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6
Q

KLF2

A

DNA binding protein expressed by quiescent naive T cells and recent thymic emigrants. Also regulates thymic egress and expression of S1PR1 and CD62L. Suppresses the transcription factor MYC.

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7
Q

FoxO1

A
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8
Q

RUNX1

A
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9
Q

Markers for naive T cells

A

CD62L-high, CD44-low

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10
Q

What intracellular signalling molecules are activated upon CD28 T cell costimulation?

A

AP-1 and NFAT1

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11
Q

Two types of intestinal CD103+ DCs

A

CDllb- cDC1s (BATF3, IRF8)
CD11b+ cDC2s (IRF4, Notch2)

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12
Q

How do SCFAs promote Treg induction?

A

Butyrate acts to inhibit histone deacetylases, which promotes acetylation of histones at the promoter of the Foxp3 locus.

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13
Q

At what age do mice begin to self-wean and consume solid food?

A

Between 16 to 18d after birth.

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14
Q

At what age do mice typically begin to produce endogenous IgA in the intestinal lumen?

In humans?

A

Around d28, which is interesting, as they have been without maternal IgA for roughly 1w.

Humans being to produce IgA around 1 month after birth, but feed on milk for much longer after that period.

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15
Q

Three main populations of intestinal Tregs

A

Neuropilin1 (Nrp1)+Rorgt- (thymus)
Nrp1+Rorgt+ (peripheral, microbiota-spec)
Nrp1-Rorgt- (peripheral, food-specific)

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16
Q

Lachnospiraceae Order/family and characteriistics

A

Phylum: Firmicutes
Class: Clostridia

obligate anerobes

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17
Q

Which cytokines promote Th1 differentiation?

A

IL-12

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18
Q

Which cytokines promote Th2 differentiation?

A

IL-2 and IL-4

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19
Q

Which cytokines promote differentiation of Th17 cells?

A

TGFB and IL-6. IL-23 helps to maintain Th17 populations but is not required for initial differentiation.

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20
Q

Bacterial metabolites that can influence T cell differentiation

A

SCFAs (Treg)
LCFAs (Th17)
secondary bile acids (inhibit Th17)

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21
Q

Which autoimmune diseases are mediated by Th17 cells and primarily through which cytokines?

A

MS/EAE (IL17A/IL17F)
Psoriasis (IL17A/F/IL-22)
Arthritis models (IL-17A)
Colitis (RORgt and IL-23 are required for colitis, but Th17 also promote tissue homeostasis)

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22
Q

What cytokines can ex-Th17 cells produce?

A

Pro-inflammatory IFNg and GM-CSF.

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23
Q

Effect of B fragilis on intestinal immunity

A

Promotes IL-10 production by Tregs through polysaccharide A (PSA)

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24
Q

Two main subtypes of ILC3s in the intestine and their functions

A

CCR6+ ILC3s exist in SLOs and TLOs and promote GALT maturation, IgA production, and limit CD4+ MSTs in an antigen-dependent manner.

T-bet+ ILC3s are diffusely present in the lamina propria, and promote tissue repair via IL-22 in response to microbial recognition.

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25
Q

gamma common chain

A

IL receptor expressed at one half of heterodimers that bind to numerous ILs, including IL2, IL4, IL5, IL7, IL9, IL15, and IL21.

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26
Q

IL7 receptor

A

heterodimer consisting of gamma common chain (IL2RG) and IL7Ra.

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27
Q

Where is IL-7 mostly expressed?

A

Mainly in lymphoid tissues such as the thymus and LNs, but lower in the spleen and BM.

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28
Q

What are the primary cells that make IL-7?

A

Thymic epithelial cells (TECs) and fibroblastic reticular cells (FRC) in LNs are important sources, whereas lymphatic endothelia in LNs5, afferent lymphatics6 and bronchus-associated lymphoid tissue of the lung7 may account for the high levels of IL-7 found in lymphatic fluid and ultimately blood serum.

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29
Q

Where is IL7Ra typically expressed?

A

Broadly in the lymphoid system, on B cell progenitors (but not mature B cells), ILCs, and throughout T cell development and maturation—although expression notably absent on selecting thymocytes and effector cells

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30
Q

At what stages of thymocyte development is IL7Ra required?

A

IL-7 signaling appears to facilitate proliferation and differentiation of these DN stages, and is necessary for gd T cell development from DN2. positive selection of DP thymocytes does not require IL-7 signaling, and these cells lack functional IL-7R expression. Cells that successfully pass selection re-express IL-7R in a multistep process dependent upon T cell antigen receptor (TCR) signaling, and the transcription factors Foxo1, Ets-1 and NF-kB

31
Q

IL7 is required for the development of what cells?

A

T cells, B cells, and ILC2 and ILC3.

32
Q

IL7R expression in T cells outside the thymus

A

In contrast to B cells, T cells continue to express IL-7R in both naive and memory states, and IL-7 signaling is critical for longterm maintenance of all T cell populations. IL-7 promotes cell survival by modulating the intrinsic pathway of apoptosis

33
Q

What happens to IL7Ra expression in T cells upon activation?

A

Following activation, T cells rapidly lose expression of IL-7Rα. Maintenance of IL-7R expression in peripheral T cells is dependent on the activity of Foxo1. The activity of Foxo transcription factors is negatively regulated by Akt-mediated phosphorylation that is activated via PI3K by upstream TCR or IL-2 signaling. This effectively uncouples effector cells from IL-7-dependent homeostatic control, relying rather on TCR and IL-2 signaling for survival and proliferation.

34
Q

CD127

A

IL7Ra

35
Q

What is the role of IL7 in non-lymphoid tissues?

A

Tissue-resident memory cells were recently recognized as important mediators of immunity in non-lymphoid organs, where they reside and are maintained. These populations do not recirculate and so their dependence on IL-7 for survival likely explains why epithelial barriers have local sources of IL-7 production.

36
Q

Which chemokine axis is involved in mammary gland / plasma cell migration?

A

CCR10 / CCL27 and CCL28

37
Q

Mechanisms of immune suppression by Tregs in periphery

A

1) anti-inflammatory cytokine secretion (IL-10, TGFB, etc.)

2) Adenosine production (high expression of CD73 and CD39 ectoenzymes increase EC adensoine, which dampens Teffs.

3) IL-2 sinks - Tregs have high IL2R expression (CD25), which can deplete IL-2 pools

4) downregulation of costim molecules on DCs

38
Q

TRECs

A

T cell Receptor Exicsion Circles - Can ID RTEs as they are produced during TCR recombination in the thymus and not copied during proliferation.

However, cells cannot be sorted by this method, as it requires amplification (qPCR).

39
Q

CD31

A

PECAM - highly expressed by RTEs in the periphery, but is also re-upregulated by Teffs

40
Q

% of Tregs in the peripheral T cell pool

A

~10% of the CD4+ pool;

up to 30% of CD4+ pool in the intestine

41
Q

How do the numbers of Treg cells in the intestine change in GF mice?

A

IN GF mice, Treg cells are decreased in the colonic LP, but increased in the SI LP. This disappears whne mice are fed an antigen-free diet, suggesting that Tregs in the SI LP mostly target food antigens.

42
Q

Different enhancers that dictate tTregs versus pTregs

A

Conserved non-coding sequence 3 (CNS3) induces tTregs by recruitment of the TF REL.

CNS1 promotes pTreg induction downstream of TGFB-SMAD pathway and retinoic acid.

43
Q

Approximately how many TCRs on the surface of a T cell?

A

~30,000

44
Q

Which cytokine can induce MHCII expression?

A

IFNg

45
Q

RSSs

A

Recombination Signal Sequences, which are adjacent to points in V/D/J gene segments in the DNA at which recombination takes place.

46
Q

TdT

A

Terminal deoxynucleotidyl transferase - adds random nucleotides to single-strand ends of DNA during DNA repair of the coding joint. This contributes to junctional diversity in V(D)J recombination. Neonatal T cells do not express TdT, and thus have lower diversity of TCRs.

47
Q

TRECs

A

T cell Receptor Excision Circles - circular DNA reads resulting from the DNA recombination process of TCR rearrangement. These reads can be found in the nuclei of RTEs.

48
Q

Number of TCR constant region genes

A

Only one for the alpha chain (Ca), and two for the beta chain (Cb), although they are very functionally homologous.

49
Q

Most variable region of a TCR

A

CDR3 (complement determining region 3)

50
Q

Which enzyme is responsible for the acidification of endosomes?

A

V-type ATPase, which resides on the cytosolic side of endosomes and lysosomes and pumps in protons from the cytosol.

51
Q

Which are the major enzymes involved in peptide processing within endosomes/lysosomes?

A

Cathepsins B, S, and L. L is the most active.

52
Q

What prevents peptide binding to MHCII molecules within the endoplasmic reticulum?

A

CD74 (invariant chain)

53
Q

CD74

A

invariant chain, prevents premature binding of peptides to MHCII within the endoplasmic reticulum.

54
Q

HLA-DM

A

HLA-DM binds to and stabilizes empty MHC class II molecules and catalyzes the release of CLIP, thus allowing the binding of other peptides to the empty MHC class II molecule

55
Q

MARCH-1

A

E3 ligase that targets cytoplasmic tail of MHCII for degradation. Its expression is upregulated by IL-10. Its expression is downregulated by TLR signalling in DCs.

MARCH-1 can also target the costimulatory molecule CD86 for ubiquitination and degradation.

56
Q

How does Kathryn Knoop define naive T cells in the gut cLP (2020)?

A

CD62L+CD44-CD69-

57
Q

What are the kinetics of naive and pTreg cell populations in the colon and SI LP discovered by Knoop 2020?

A

Naive T cell populations peak around ~d10, and decrease as a percentage of CD3+CD4+ cells from there.

pTregs being to appear at ~d15, and peak at weaning (d24), before declining. Similar kinetics for the SI ans the colon LP.

58
Q

how might FcRn route IgG-ICs to antigen-presenting-assocaited endosomes?

A

FcRn has been shown to co-localize with CD74 (invariant chain (iI)), which is also assocaited with newly synthesized MHCII molecules. The intracellular tail of iI routes these two molecules to similar endosomal/lysosomal compartments.

59
Q

InduRag mice

A

These mice lack Rag expression at steady state and thus have no peripheral T cell compartment. Treatment with Tamoxifen leads to Rag expression and population of the periphery with T cells

60
Q

In the neonate, what dictates the trafficking of RTEs to the intestine before d11?

A

Integrin B7, not not CCR9.

61
Q

Antibody repertoire of Cbir-Tg mice

A

No Cbir-specific IgG titers, but high Cbir-specific IgA titers

62
Q

Long-lived memory Th1 cell phenotype

A

CD27+ low expression of T-bet and Ly6c

63
Q

Summarize Tim Hand 2012 findings

A

Transfer of Cbir-Tg T cells to SPF mice - Cbir+ T cells reamained naive. When infected with T. gondii, Cbir+ T cells were activated and developed into a long-lived Th1 memory population that produced IFNg in vitro.

64
Q

Differences in Th17 gene expression in Th17 cells isolated from an inflammatory environment vs those isolated from a homeostatic environment

A

Unlike the gene expression signature of pathogenic Th17 cells isolated from an inflammatory milieu, homeostatic Th17 cells have a significantly lower level of pro-inflammatory transcripts including Tnf, Ifng and Il23a, and an up-regulated expression of anti-inflammatory genes, such as Ctla4, Icos and Il22

65
Q

Which chemokine axis is responsible for the accumulation of positively selected SP thymocytes into the medulla?

A

CCR7 / CCL21

66
Q

Distribution of CD103+CD11b- and CD103+CD11b+ MNPs within the murine intestine

A

CD103+CD11b- : mostly in the SI LP

CD103+CD11b+: mostly in the cLP and GALT (PPs, ILFs, etc)

67
Q

How might SFB perferentially induce Th17 responses?

A

SFB adherence induced the expression of serum amyloid proteins (SAA1/2) and the reactive oxygen–producing protein Duox2 in epithelial cells (7, 51, 117). SAA1, in particular, directly enhances IL-17A and IL-17F induction by Th17 cells and also acts on DCs to promote Th17 induction

68
Q

How does ATP sensing alter mucosal immunity?

A

EC ATP is produced by the GMB. GF mice have sig reduced fecal ATP.

Gavaging mice with ATP leads to induction of Th17 responses in the gut. ATP is sensed by the P2X receptor on CD70-highCD11c-low DCs

69
Q

Effect of GMB tryptophan metabolism on mucosal Immunity

A

tryptophan is metabolized by GMB to indole and related molecules. Indole is recognized by AhR, and leads to expansion of ILCs and IL-22 production.

70
Q

Immunoregulatory expression of RORgt+ Treg cells in cLP

A

High levels of IL-10, CTLA-4.

71
Q

Tissue frequencies of Th17 and RORgt+Tregs in LP

A

These two cell types are typically in inverse frequencies - high frequencies of Th17 in the SI, and high frequencies of RORgt+Tregs in the colon.

72
Q

How can intestinal RORgt+ Tregs regulate Teffs through CTLA-4 expression?

A

Treg CTLA-4 may directly remove CD80/86 from APC membranes.

Recent study showed that cLP Tregs cluster with MHCII+CD11c+ APCs, and that these clustered cells express higher levels of CTLA-4 than non-clustered cells.

73
Q

Which clusters of Clostridia have been suggested to be the most influential in Treg induction?

A

Clostridia subclusters IV and XIVa

ACE (2 decks)

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