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Immunology > Week 4 > Flashcards

Week 4 Flashcards

1
Q

What nonhematopoietic cell is located directly beneath the subcapsular sinus in the lymph node?

A

Marginal reticular cells

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2
Q

LTo cells

A

Lymphoid tissue organizer cells. These cells receive signaling from LTi cells in the developing fetus to form lymph nodes and develop into the fibroblastic reticular cells (FRCs) in the murine lymph nodes.

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3
Q

fDC chemokine expression in the dark and light zone

A

LZ FRC: CXCL13+CXCL12-

DZ FRC: CXCL13-CXCL12+

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4
Q

What is unique about the expression marker patterns of fDCs?

A

They do not express PDPN

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5
Q

What is the function of the conduit network in lymphoid organs?

A

lymph-borne antigen rapidly enters the LN con- duit network, where it can be directly sampled by resident dendritic cells (DCs) and follicular B cells through gaps in the FRC sheath

Likewise, soluble chemokines are rapidly delivered via the conduit network to the ablumenal surface of the HEV, whereupon these molecules are transcytosed and decorate the vascular lumen, leading to increased lymphocyte homing

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6
Q

2 methods of blocking fluid absorption across the SI epithelium in Chang et al

A

10% solution of high molecular weight polyethlene glycol (PEG) in drinking water (osmolarity) or oral gavage with amiloride hydrochloride (blockage of Na+/H+ exchangers across membrane).

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7
Q

Cellular structure of PP High Endothelial Venules

A

An intact PP HEV is structurally com- prised of MAdCAM-expressing endothelium closely encircled by a ring of perivascular FRCs

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8
Q

S1P / S1PR axis in lymphocytes

A

S1P is a signaling molecule highly expressed in the blood and lymph, while its receptor is highly expressed on circulating lymphocytes. Ligation of S1P leads to its internalization, which allows lymphocytes to traverse into S1P-low lymph nodes, where the receptor is eventually re-upregulated to allow for egress to the lymph.

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9
Q

FTY720

A

S1PR1 agonist that acts an immunosuppressant, downregulating s1PR expression on lymphocytes and preventing their egress from the lymph nodes.

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10
Q

How are Peyers Patches affected by the disruption of fluid absorption?

A

Disruption of fluid flow from intestine leads to an inability for cells to establish polarization - MaDCAM-1 is therefore expressed evenly on both

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11
Q

What is the first step of phagocytosis of dying cell?

A

inositol phospholipids and phosphoinositide 3-kinases (PI3Ks) promote the fusion of intracellular vesicles, such as recycling endosomes and possibly portions of endoplasmic reticulum with the plasma membrane near the site of the developing phagosome.

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12
Q

What are some ways in which efferocytosis prevents inflammation?

A

AC binding to the efferocyte receptor T cell immunoglobulin
mucin receptor 1 (Tim1) suppresses the production of tumour necrosis factor (TNF), il-6 and CC-chemokine ligand 5 (CCl5) by blocking activation of nuclear factor-κB (NF-κB), whereas AC binding to the efferocyte receptor stabilin 2 stimulates the production of transforming growth factor-β (TGFβ)

Binding of ACs to the protein tyrosine kinases mer proto-oncogene tyrosine kinase (merTK) and AXl can suppress Toll-like receptor (Tlr) and type 1 interferon-mediated proinflammatory signalling pathways

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13
Q

What are the three overall outcomes of efferocytosis?

A

termination of inflammatory responses,
promotion of self-tolerance
and activation of proresolving pathways.

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14
Q

What are the three waves of monocyte development and which cells do they ultimately produce?

A

Wave 1 - “Primitive” - microglia
Wave 2 - “Transient Definitive” - Tissue-resident macrophages
Wave 3 - “Definitive” - Monocyte-derived macrophages

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15
Q

What cell markers are used to define classical and non-classical monocytes?

A

Humans:
CD14+CD16++ = Non-classical monocytes
CD14++CD16- = Classical monocytes

Mice:
Ly6C-hi = classical monocytes
Ly6C-lo = non-classical monocytes

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16
Q

What are the functions of classical monocytes?

A

phagocytic, proteolytic, cell debris removal

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17
Q

What are the functions of non-classical monocytes?

A

myofibroblast accumulation, angiogenesis, collagen deposition

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18
Q

What chemokine do monocytes use to emigrate into the circulation?

A

CCL2

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19
Q

What are functions of Ly6C-low circulating monocytes?

A

patrol blood vessel lumen. may extravasate and become alternatively activated macrophage in tissue to promote tissue repair.

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20
Q

What are the functions of Ly6C-hi circulating monocytes?

A

Can replenish Langerhans cells and microglia in instances of depletion. Can become CX3CR1+ MNPs in the gut lamina propia.
In inflamed tissues, can become TIP (TNF/iNOS producing) or inflammatory DCs. Can be released from splenic reserve during myocardial infarction.

In the absence of inflammation, they may return to the bone marrow and become Ly6C-lo circulating monocytes.

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21
Q

How are Ly6C-high monocytes recruited from the bone marrow?

A

TLR ligands and type I IFNs released during Listeria infection can promote monocyte emigration from the BM.

CCL2 from fibroblasts can also drive monocytes to emigrate from the BM and enter tissues. In the case of a Th1 response, local Th1 cells producing IFNg will prompt entering monocytes to become M1 macrophages

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22
Q

What are four factors that contribute to Tissue resident macrophage identity?

A 
Origin (BM vs embryo)
Inflammation (presence or absence of 
PAMPs)
Local Environment (other cell types)
Time
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23
Q

What transcription factors contribute to the core macrophage program?

A

Pu.1
c-MAF
MAFB
ZEB2

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24
Q

Name three types of macrophaes in the spleen and their functions

A

Red pulp macrophages - recycling of RBCs
Marginal Zone Macrophages - contribute to TI B cell responses and phagocytose BB pathogens
Metallophilic Mqs - contribute to activation of CD8+ T cells & phagocytose BB pathogens

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25
Q

What are the roles and metabolic programs of M1 macrophaes?

A

Proinflammatory, microbicidal, anti-tumoral.
Express high CXCL10, MHCII and CD86.

Primarily metabolic program is glycolysis.

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26
Q

What are the roles and metabolic programs of M2 macrophaes?

A

Antiinflammatory, Immunoregulation,
Tissue remodeling, Proliferation, Protumoral

Make lots of IL-10.

Display lots of IL-1R decoy.

Mostly OXPHOS metabolism.

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27
Q

What is the difference between intrinsic and extrinsic apoptosis?

A

Apoptosis can be triggered by the activation of a mitochondrial pathway by cellular stress (intrinsic apoptosis) or through the activation of death receptors at the cell surface (extrinsic apoptosis)

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28
Q

How is DNA dealt with during apoptosis?

A

In healthy cells, caspase- activated DNase (CAD) exists in complex with its inhibitory chaperone ICAD and remains constitutively inactive. Active caspase 3 cleaves ICAD promoting CAD homodimerization, nuclear translocation and DNA hydrolysis between nucleosomes. Nuclear pieces are then neatly packaged with cytoplasm into apoptotic bodies that are eventually digested during efferocytosis

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29
Q

How is cytosolic DNA recognized in the cell?

A

cyclic GMP–AMP synthase (cGAS) leads to activation of STING and type 1 interferon response

and the inflammasome component AIM2 leads to inflammasome activation and IL1B processing.

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30
Q

What cytokines are released from non-apoptotic dying cells?

A

IL-1 family cytokines such as IL-1a, IL-33, and IL-36.

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31
Q

What are some cell membrane-associated eat-me signals on apoptotic cells?

A

Phosphatidylserine, Calreticulin

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32
Q

What are do-not-eat-me signals on viable cell membranes?

A

CD24, CD31, CD47, MHCI

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33
Q

What changes happen in the efferocytic cell upon ligation of phosphatidylserine receptor ligation?

A

an anti-inflammatory response mediated by the secretion of IL-10, TGFβ and prostaglandins, and the active inhibition of the production of proinflammatory cytokines, including tumour necrosis factor (TNF) and IL-1β

34
Q

What are the costimulatory molecules on DCs and T cells for MHC II antigen presentation?

A

CD80 and CD86 (DCs), recognized by CD28 (T cells).

35
Q

Th2 cell transcription factor

A

GATA3

36
Q

Th1 cell transcription factor

A

T-bet

37
Q

Tfh cell transcription factor

A

Bcl6

38
Q

What are the three types of antigens that can be cross presented by DCs and which DC subsets present them?

A

pathogen-associated (cDC1s)
soluble (both cDC1 > cDC2)
cell-associated antigen (cDC1)

39
Q

Markers expressed by cDC1s

A

XCR1
CLEC9A
CD8

40
Q

Transcription Factors for cDC1s

A

IRF8

Batf3

41
Q

Markers expressed by cDC2s

A

CD11b
SIRPa
CD4

42
Q

Transcription Factors for cDC2s

A

IRF4,
Notch2
KLF4

43
Q

What are the differences between the two subsets of cDC2s?

A

cDC2A - anti-inflammatory, downregulate CD86, T-bet+

cDC2B - proinflammatory, make TNFa and IL-6, T-bet-

44
Q

Which environmental cues infrom cDC2A development?

A

Lymphotoxin B, Retinoic Acid

45
Q

Which DC subsets express which C-type lectin receptors?

A

CLEC9A: cDC1
CLEc12A: cDC1s and cDC2B
CLEC4A: cDC2A/B

46
Q

Summary of the differences in antigen presentation between cDC1s and cDC2s

A

Conventional type 1 dendritic cells (cDC1s1) are thought to perform antigen cross-presentation required to prime CD8 T cells while cDC2 are considered specialized for priming CD4 T cells

47
Q

What are the two markers that define mouse classical DCs?

A

CD135 (Flt3), CD11c

48
Q

cDC1 v cDC2 percent distribution in periphery and LOs

A

cDC1s are 30% of periphery and 40% of lymphoid cDCs. PP and thymus are exceptions where cDC1s are enriched.

49
Q

What two markers define the double negative stages DN1 - DN4 of thymocytes in the thymus?

A

(CD44) and CD25 (IL-2Ra)

CD25-CD44+ = DN1
CD25+CD44+ = DN2
CD25+CD44- = DN3
CD25-CD44- = DN4
50
Q

What transcription factor commits a T cell precursor to the T cell fate?

A

Bcl11b, which coincides with rearrangement of the TcrB and Tcrg loci.

51
Q

Regions of thymocyte development in the thymus

A

Cortex > subcapsular region > corticomedullary junction

52
Q

Breakdown of thymocyte CD4/CD8 expression in thymus

A

5%DN, 80% DP
10% CD4 SP
5% CD8 SP

53
Q

CD25

A

IL-2Ra chain

54
Q

CD44

A

c-kit

55
Q

Critical signaling axis for T cell lineage commitment

A

Notch1 / Delta

Ligands are Delta and Jagged, also cell surface expressed (juxtacrine signaling) on stromal cells.

Notch signaling is cool because the intracellular portion will cleave on ligation and translocate to the nucleus and act as transcription factor.

56
Q

How is Notch signaling important in lymphocyte development

A

Promotes T cell fate and at the same time suppresses other fates.

57
Q

What other cells can DN2 thymocytes develop into?

A

DCs, NK cells, and Mast cells. This is prevented by Notch signaling.

During DN2 stage, TCR rearrangement occurs and this limits the cell’s lineage choices.

58
Q

Which TCR chain is rearranged first?

A

TCRB.

59
Q

What stage of T cell development does TCRa chain rearrangement occur and what is special about it?

A

During DN stage. T cell has multiple attempts at rearranging TCRa to find a successful chain.

60
Q

What are the three types of selection in T cell development?

A

B chain selection (DN3 -> DN4), positive selection and negative selection (DP)

61
Q

intracellular signaling required for B selection in T cell development

A

Src Kinases

62
Q

intracellular signaling required for positive/negative selection in T cell development

A

ZAP-70

63
Q

how would you design an experiment to study intracellular signaling for T cell development?

A

create a knock out mouse and look for CD8 and CD4 expression in both the thymus and peripheral LNs. Proteins involved in Beta selection will lead to DN cells only in both organs, while those involved in positive/negative selection will lead to DP in thymus and only DN in LNs.

64
Q

How is functional rearrangement of B-chain detected?

A

It must mediate a tonic signal via CD3 ITAMs at the cell surface (Pre-Talpha, CD3ko mice have a block at checkpoint #1)

65
Q

What is the function of checkpoint #1 in T cell development?

A

To assess whether a functional B-chain has been assembled through rearrangement.

66
Q

What are the consequences of successful B-selection in T cell development?

A

Proliferation and differentiation of DN thymocytes that express a functionally rearranged B-chain.

67
Q

What stimulates the pre-TCR to signal in checkpoint #1?

A

No known ligand, but oligomerization has been reported to signal. pre-TCR can mediate signals without EC portion.

68
Q

What is the function of checkpoint #2 in T cell development?

A

Assess 1) whether alpha-chain is functionally rearranged

2) whether TCR is self-MHC restricted
3) whether the TCR is auto-reactive

69
Q

What are the consequences of passing checkpoint #2 in T cell development?

A

Thymocytes mature to functionally competent SP T cells ready to egress and to establish a self-MHC-restricted, less-autoreactive T cell pool with matched coreceptors and functional potential in the periphery.

70
Q

What happens if there is no interaction between TCR and MHC molecule in checkpoint #2 of T cell development?

A

Absence of interaction leads to apoptosis (death by neglect)

DP cells only exist for 3-4 days

71
Q

How can you check peptide specificty for T cell development?

A

Fetal thymic organ culture. Use TAP-deficient mice (do not deliver peptides to MHC class I) and remove thymus and place in culture. Then, add different peptides to culture, which will bind to MHC class I molecules transiently expressed on the surface.

72
Q

How did Palmer et al prove peptide selection affinity for T cell development?

A

Use OTI-I T cells with TCR specific for OVA peptide (SIINKFEKL) in fetal thymic organ culture and mutate to varying degrees. High-affinity interaction T cells undergo apoptosis, as well as T cells with no affinity (using unrelated VSV peptide).

73
Q

How do cTECs present peptides on MHC II molecules?

A

In cTECs (cortical thymic epithelial cells), macroautophagy appears to be a specific mechanism for shuttling cytoplasmic material (endogenous antigens) into the MHC II (through the macroautophagosome) compartment for presentation and selection of the CD4 T cell repertoire.

74
Q

How is the proteasome different in cTECs?

A

In cTECs (cortical thymic epithelial cells), a specific subunit (Beta-5t) of the proteasome results in processing of peptides with a low binding affinity for MHC; this less-stable pMHC complex is thought to promote selection of MHC class I-restricted CD8 T cells

75
Q

What are the two theories on why TCR signaling needs MHC molecules?

A

“Germline model” - conserved amino acids in TCR may impose MHC restriction

“Selection model” - coreceptor sequestration of Lck imposes MHC restriction - Van Laethem et al 2012

76
Q

What is the stochastic/selection model of CD4/CD8 lineage commitment?

A

No directional infromation comes to the T cells during the positive selection interaction with MHC. CD4 or CD8 is randomly switched off (half wrong, half correct), but the cells still need TCR plus coreceptor interaction with MHC to complete positive selection. “Wrong” choice leads to death by neglect.

77
Q

What is the instructive model of CD4/CD8 lineage commitment?

A

The interaction of the TCR with either MHC I or II is read by the cell so that the correct decision is made (i.e. positive selection on MHC II instructs the cell to switch off CD8, etc.)

78
Q

What are day 3 thymectomy experiments?

A

If you remove thymus at day 3 (only), mice will develop autoimmune diseases. (Non-Tregs develop before day 3, Tregs develop after day 3)

79
Q

How to define Tregs phenotypically?

A

Foxp3 and CD25 (IL-2Ra)

80
Q

How are Tregs and IELs generated in the thymus?

A

Agonist self-peptide selection (high-affinity) - no clonal deletion despite high affinity recognition of pMHC in thymus

Immunology (17 decks)

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