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Immunology and Infection > Immune Cell Migration > Flashcards

Immune Cell Migration Flashcards

1
Q

what is the afferent lymphatic?

A

into the lymph nodes

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2
Q

what is the efferent lymphatic?

A

out of the lymph nodes

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3
Q

what is a key problem for the immune system?

A
  • pathogens can establish anywhere
  • Needs T and B cells to detect the pathogens
  • these cells are highly specific and therefore are very rare
  • to solve this immune cells circulate the blood and the lymph
  • to get cells to the right place you need chemokines and adhesion molecules
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4
Q

what are chemokines?

A

chemotactic cytokines

  • secreted molecules that bind to cell surface GAGs
  • chemokines bind back to the cells that produce
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5
Q

how is a chemokine gradient formed?

A
  • have the highest chemokine concentration on its surface
  • any that dont bind become tethered to the ECM proteins
  • tethered chemokines form immobilised concentration gradient
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6
Q

how are chemokines sense?

A
  • target cells express chemokine receptors

- chemokine receptors are coupled to heterotrimeric G proteins

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7
Q

what is the structure of a chemokine receptor?

A
  • alpha, beta and gamma
  • alpha is bound to GDP
  • when chemokine binds it causes a conformational shift, causes activation
  • G proteins associate
  • exchange GDP for GTP which initiates a signalling cascade
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8
Q

what happens when a chemokine binds to a receptor?

A

there is cytoskeletal rearrangement and the cell migrates

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9
Q

what is a CC chemokine?

A
  • towards the end terminus they have cysteine residues

- involved in disulphide bonds

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10
Q

what is a CXC chemokine?

A

got cysteine residues but with any amino acid in between

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11
Q

what kind of leukocytes can be found in the blood?

A

T cells; CD4 and CD8, B cells, neutrophils, monocytes

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12
Q

what is lymphatic circulation?

A
  • lymph transmits signals from tissues to draining lymph nodes
  • carry lymph from peripheral tissues to draining lymph nodes
  • transports immune cells, intact pathogens, free antigens
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13
Q

where are adaptive immune responses initiated?

A

in draining lymph nodes

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14
Q

why does the lymph node also have blood vessels?

A
  • T cells can either circulate or they can interact and migrate into the lymph node
  • this would be the HEV (high endothelial vessel)
  • carry signals, dendritic cells which interact with T cells
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15
Q

how do T cells exit the blood and enter the lymph node?

A
  • blood vessels convert into HEV
  • T cells can interact
  • EXTRAVASATION
  • blood moves quickly, cells need to slow down
  • rolling, activation, firm adhesion, transmitgration
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16
Q

what is rolling (stage 1 of extravasation)?

A
  • lectin dependent
  • Naive T cells express cell surface protein L selectin (CDG2L)
  • binds to carbohydrates on endothelial cells on HEV, recognises the glycoproteins
  • different lymph nodes can have different glycoproteins
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17
Q

what are HEV surface glycoproteins called in rolling?

A

‘addressins’

18
Q

what are the addressins found on HEV in rolling?

A

GlyCAM

CD34

19
Q

what are PNAd in rolling?

A
  • peripheral node addressins

- addressins for peripheral lymph nodes are PNAd

20
Q

in rolling what is the interaction between L selectin and PNAd like?

A

weak/transient (on/off kinetics)

21
Q

what is activation and firm adhesion (stages 2 and 3 of extravasation)?

A
  • chemokines convert rolling to firm adhesion
  • have chemokines on the surface of HEV
  • display 2 chemokines on its surface GAGs (CCL19 and CCL21)
  • naive T cell express CCR7, the receptor for CCL19 and CCL21
22
Q

how does chemokine signalling lead to integrin activation in activation and firm adhesion?

A
  • T cells have integrin LFA1 on their surface
  • endothelial cells have adhesion molecule ICAM1
  • LFA1 has alpha1 and beta2
  • LFA1 binds to ICAM1
  • chemokines signalling activates and causes a conformational shift in surface integrin’s
  • conversion to high affinity ICAM1 binding = firm adhesion
23
Q

what structure do integrins have?

A

heterodimers

alpha and beta subunits

24
Q

why does activation and firm adhesion in extravasation need signalling?

A

in the absence of signalling LFA1 and ICAM1 the interaction is very weak, LFA1 starts in a low affinity conformation

25
Q

what is transmigration in extravasation?

A
  • naive T cells produce proteases to transmit between endothelial cells and through the basement membrane
  • metalloproteases
26
Q

how do T cells have directed movement in the lymph node?

A
  • T cells need to get to the T cell zone
  • T cell zone contains specialised fibroblasts that produce CCL19 and CCL21
  • CCL19/21 gradient attracts CCR7+ T cells to the T cell area
27
Q

how do dendritic cells have directed movement in the lymph node?

A
  • tissue denritic cells upregulate CCR7 in response to PAMPs and inflammatory cytokines
  • responsive to the same chemokine as T cells
  • will go to the same area as the T cells and can interact
28
Q

how do B cell have directed movement in the lymph node?

A
  • B cell zone contains fibroblasts that produce CXCL13

- CXCL13 gradient attracts CXCR5 B cells to B cell follicles

29
Q

what happens when there is prolonged exposure to chemokines in the lymph node?

A

causes transient down-regulation of chemokine receptors

30
Q

how do leukocytes leave the lymph node?

A
  • leaving the lymph node (S1P gradient)
  • become responsive to SIP
  • high outside the lymph node and forms a gradient
  • exit via efferent
31
Q

what is normal unifected tissue like?

A
  • under homeostatic conditions blood immune cells rarely enter normal tissues
  • unlike HEV normal blood vessel endothelial cells have low levels of adhesion molecules and chemokines
32
Q

how is change in blood vessels during infection initaited?

A
  • pathogen recognised by macrophages
  • PAMPs recognised through PRR
  • macrophages produce cytokines
  • blood vessels have TNF receptors and become activated
33
Q

what molecules are produced to attract immune cells through the blood vessels during infection?

A
  • TNF upregulates adhesion molecules on endothelial cells
  • activated tissue resident macrophage produce inflammatory cytokines
  • chemokines transcytose the endothelial cell barrier
  • neutrophils express CXCR1 and CXCR2, receptors bind CXCL8
  • monocytes expressed CCR2, receptor binds CCL2
  • chemokine receptor signalling causes the activation of integrins
34
Q

what happens when blood vessels have TNF receptors and become activated?

A
  • causes blood vessels to start expressing high levels of selectin adhesion molecules
  • neutrophils and monocytes have glycoproteins on their surface which bind to the selectins
  • result in the rolling of leukocytes
35
Q

what inflammatory cytokines will resident macrophage produce?

A

CXCL8

CCL2

36
Q

what happens when integrins are activated through chemokine receptor signalling?

A
  • integrin LFA1 is expressed by neutrophils and monoccytes when the receptors and ligands bind
  • recognise strongly and get firm adhesion
  • migration across
37
Q

how are pathogens killed?

A
  • neutrophils phagocytose pathogens and secrete toxic granules
  • netocytosis
  • monocytes develop into macrophages
38
Q

what are homeostatic chemokines?

A

constitutively expressed to promote immune cell rolling to target organs

39
Q

what are inflammatory chemokines?

A

induced by infections/inflammation to recruit immune cells to sites of inflammation

40
Q

what do you need chemokine signatures for different infections?

A

different pathogens need to be controlled with different immune response

41
Q

what chemokines are produced for a viral infections?

A
  • induce interferom gamma production
  • sitmulate macrophages to make CXCL9/CXCL10/CXCL11
  • they bind CXCR3
  • recruit antiviral T cells and NK cells
42
Q

what chemokines are produced for parasitic worm infections?

A
  • induce interleukin-13 production
  • IL-13 stimulates macrophages to make EOTAtuxius
  • Eotaxius bind to CCR3 to recruit anti-parasite eosinophils

Immunology and Infection (13 decks)

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