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MIMM 314 > Lecture 13 - Mechanisms in T Cell Activation (1) > Flashcards

Lecture 13 - Mechanisms in T Cell Activation (1) Flashcards

1
Q

what do lymphatics allow for?

A

allow for immunosurveillance

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2
Q

what is immunosurveillance?

A

appropriate T cells are found in appropriate locations

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3
Q

are the central lymphoid organs connected to lymphatics?

A

no - the central lymphoid organs are isolated from the environment and peripheral immune system

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4
Q

what happens to lymph in secondary lymphoid organs?

A

in LN: lymph is filtered before returning to circulation

in spleen: no lymph circulation

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5
Q

what is filtered from lymph when it goes thru LN?

A

LN filters ANTIGENS from the lymph

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6
Q

why do the LN filter antigens from the lymph? (2)

A
  1. for recognition by T and B cells
  2. for destruction by macrophages to prevent spread
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7
Q

2 routes for T cells to enter LN

A
  1. enters via blood thru HEV and stays in that LN
  2. enters via afferent lymphatics from another LN
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8
Q

Afferent lymphatics

A

lymph flowing TOWARDS LN

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9
Q

Efferent lymphatics

A

lymph flowing AWAY from LN

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10
Q

how is directionality determined in lymphatics?

A

by 1-way valves

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11
Q

what are the LFA adhesion molecule?

A

alpha and beta subunits of integrins

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12
Q

what is the ligand for LFA/integrin?

A

ICAM from Ig superfamily

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13
Q

structure of cells in the HEV

A

squamous endothelial cells

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14
Q

4 general stages in leukocyte migration

A
  1. rolling
  2. activation
  3. adhesion
  4. diapedesis
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15
Q

why does the T cell require adhesion molecules during leukocyte migration?

A

adhesion molecules act like velcro so the T cell can slow down for diapedesis

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16
Q

where are leukocytes migrating when they cross the HEV?

A

from the peripheral pool to the marginal pool, i.e. into the LN cortex

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17
Q

what allows endothelial cells in HEV to express adhesion molecules?

A

cytokines activate them

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18
Q

what adhesion molecule mediates the first step of leukocyte migration: ROLLING?

A

L-selection aka CD62L

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19
Q

what is the role of L-selection/CD62L?

A

to tether the T cell on the endothelium

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20
Q

what adhesion molecule mediates the third step of leukocyte migration: ADHESION?

A

Integrins aka LFA-1

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21
Q

what happens to the T cell during adhesion?

A

T cell loses its round shape and gets in tighter contact with HEV

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22
Q

what occurs during DIAPEDESIS?

A

T cell migrates btwn endothelial cells

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23
Q

speed of T cell during tethering
and speed of T cell during rolling

A

tethering: 4000 microns/sec

rolling: 40 microns/sec

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24
Q

how long does leukocyte migration take?

A

10 min

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25
Q

what are naive T cells?

A

not activated/not exposed to antigen/in resting state

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26
Q

in general, what do naive T cells express?

A

homing receptors that binds SELECTINS or ADDRESSINS on endothelial cells in SLO

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27
Q

specifically, what does L-selectin/CD62L on naive T cells bind at the HEV

A

binds SLeX (carbohydrate) motif on CD34 and GlyCAM-1 on HEV

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28
Q

specifically, what does L-selectin/CD62L on naive T cells bind at the mucosal endothelium

A

binds SLeX on MAdCAM-1 on mucosal endothelium

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29
Q

what type of molecules are CD34 and GlyCAM-1?

A

addressin

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30
Q

do naive T cells express HIGH or LOW levels of CD62L? why?

A

HIGH levels of CD62L bc they need to be able to tether to HEV and reach LN

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31
Q

what happens to expression of CD62L once the T cells enter the LN?

A

upon entry to the LN, T cells meet an antigen and become activated and DOWNREGULATE expression of CD62L

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32
Q

why is CD62L downregulated in activated T cells?

A

so it can leave the LN and go to non-lymphoid tissues

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33
Q

what do CD62L levels indicate?

A

indicates which T cells have already seen their antigen or are about to see their antigen

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34
Q

what do integrins favour?

A

integrins favour cell adhesion to STABILIZE cell interactions

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35
Q

in the LN, how do T cells become activated?

A

T cell interacts with APC to meet its antigen

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36
Q

how does the T cell interact with APC?

A

ICAM-1 on APC binds LFA-1 on T cell

37
Q

what is a unique feature of integrins/LFA-1?

A

must be activated!

38
Q

describe process of activation of integrins/LFA-1 via TCR

A
  1. APC binds to T cell via ICAM-1/LFA-1 occurs 1st
  2. Then p:MHC binds TCR 2nd
  3. LFA-1 changes conformation of alpha and beta subunits to change conformation to be more tightly bound to ICAM-1
  4. now LFA-1 has INCREASED AFFINITY to LN
39
Q

2 ways that T cells become activated to increase affinity of integrin to LN

A
  1. TCR
  2. SLCs (CCL21/19)
40
Q

3 molecules necessary for T cell entry into LN

A
  1. Integrin/LFA-1
  2. L-selection/CD62L
  3. CCR7
41
Q

describe the process of activation of integrins/LFA-1 via SLCs in HEV

A
  1. circulating T cell enters LN via HEV
  2. L-selectin binds GlyCAM-1 or CD34 to allow rolling on HEV surface
  3. chemokine receptor CCR7 on T cell binds CCL19/21 on HEV to give activating signal
  4. LFA-1 changes conformation to increase affinity to ICAM-1
  5. allows for diapedesis
42
Q

what type of enzyme is involved in diapedesis?

43
Q

what would happen if there was no chemokine signal to activate LFA-1?

A

LFA-1 would bind less strongly to ICAM-1 and T cells would not stop long enough for diapedesis

44
Q

how was T cell homing discovered?

A

intravital microscopy

45
Q

what type of receptor is CCR7 and other chemokine receptors?

46
Q

How does CCR7 expression change once T cells have seen their antigen? why?

A

CCR7 expression is downregulated bc once the cells have seen their antigen, want to encourage them to leave

47
Q

what happens in B zones?

A

CXCL13 attracts Tfh and B cells via CXCR5

48
Q

what happens in T zones?

A

T zones produce T cell and DC attracting chemokines, CCL19/21, to interact with CCR7

49
Q

can peripheral tissues also recruit naive T cells?

50
Q

example of peripheral tissues that recruit naive T cells

A

lamina propria in the gut

51
Q

describe the recruitment of naive T cells in lamina propria

A
  1. on the gut mucosal endothelium, L-selectin on T cell binds MAdCAM-1 on endothelial cell which also binds alpha4:beta7 on T cell
  2. once cells can extravasate into lamina propria, E-cadherin on epithelium binds alphaE:beta7 on T cell
52
Q

purpose of anti-integrin therapies

A

target various alpha:beta integrins to affect cellular interactions, limiting movement and downstream activation

53
Q

what pathway allows T cells to exit lymphoid organs?

A

sphingosine 1 phosphate (S1P)

54
Q

what are S1P receptors?

A

GPCRs that target the lipid signaling molecule S1P

55
Q

Describe the exit of T cells from the thymus and spleen with S1P pathway

A
  1. T cells express S1PR1
  2. increasing gradient of S1P as you leave the thymus/spleen
  3. T cells can exit into blood
  4. S1PR1 is downregulated
56
Q

Describe the exit of of T cells from the LN and peyer’s patch with S1P pathway

A
  1. T cells express S1PR1
  2. increasing gradient S1P as you leave the LN/PP
  3. T cells can exit into efferent lymph
  4. S1PR1 is downregulated
57
Q

what is FTY720 treatment?

A

inhibits egress of T cells from lymphoid organs as an immunosuppressant for MS treatment

57
Q

why do we want to prevent egress in MS?

A

So T cells stay in LN and cannot leave to destroy the brain

58
Q

relative expression of L-selectin in naive vs effector T cells

A

high in naive, absent in activated

59
Q

relative expression of LFA-1 in naive vs effector T cells

A

present in naive, higher in activated

60
Q

relative expression of CD44 in naive vs effector T cells

A

present in naive, higher in activated

61
Q

what does CD44 bind?

A

CD44 binds hyaluronic acid in ECM

62
Q

why is CD44 expressed more in activated T cells?

A

so they can bind well at inflammatory sites where ECM is

62
Q

what is VLA?

A

Very Late Antigen

63
Q

relative expression of VLA-4 in naive vs effector T cells

A

none in naive, lots in activated

64
Q

why is there a lot of VLA-4 in activated T cells?

A

to allow homing of T cells to inflamed sites

65
Q

overall role of adhesion molecules in naive T cells

A

so T cells can access lymphoid tissue for stimulation

66
Q

overall role of adhesion molecules in memory T cells

A

so T cells can leave lymphoid organs and access sites of inflammation

67
Q

what does location of T cell priming in the body determine?

A

the induction of peripheral homing molecules to the skin and small intestine

i.e. the location of T cell priming/activation indicates the local adhesion and chemotaxis events that allow for specific tropism

68
Q

T cell activation in skin-draining SLOs leads to:

A

T cell activation in skin-draining SLOs preferentially programs the upregulation of skin homing molecules

69
Q

role of vitamin D

A

Vitamin D metabolites which are catalysed by sunlight may induce CCR10 expression

70
Q

where do developmental cues come from after migrating to non-lymphoid tissues?

A

the tissue microenvironment

71
Q

describe the circulation of T cells

A

active recirculation btwn blood, lymphoid, and non-lymphoid tissues

72
Q

describe T cell scanning for T cell activation

A

in secondary lymphoid tissues, T cell scans for appropriate p:MHC that matches its TCR

73
Q

what happens if the p:MHC does not match the TCR?

A

T cell will exit the LN and re-circulate to start over

74
Q

what happens if the p:MHC does match the TCR?

A

T cell will stop

75
Q

describe the experimental evidence of co-stimulation

A

transgenic TCR specific to PCC peptide presented by I-Ek MHC

Condition 1: normal APC presenting PCC on I-Ek
- T cells activated

Condition 2: chemically fixed APC that has PCC and I-Ek but cannot upregulate/induce new molecules
- T cells not activated

76
Q

what does it mean that condition 2 cannot activate T cells?

A

only has p:MHC signal so it cannot upregulate co-stimulatory molecules

77
Q

what are the 2 signals involved in T cell activation?

A

Signal 1: Ag/TCR trigger
Signal 2: co-stimulation

78
Q

what happens if a cell receives only signal 1?

A

T cell tolerance

79
Q

when is T cell tolerance helpful?

A

to limit/block aberrant responses like autoimmunity

80
Q

what costimulatory molecules does APC upregulate?

A

upregulates B7-1/CD80 and B7-2/CD86

81
Q

what do B7 molecules bind?

A

B7 on APC bind constitutive CD28 on T cells

82
Q

what type of molecules are B7 molecules and CD28 molecules?

A

Ig superfamily

83
Q

4 ways that APCs can be activated to induce B7 expression

A
  1. infection
  2. stress
  3. cellular damage
  4. recognition by innate receptors
84
Q

the ________ status of APC determines the signal

A

the activation status of APC determines the signal

85
Q

are signal 1 and signal 2 sufficient alone?

A

NO –> they are each insufficient for T cell activation, need both

86
Q

what happens if you only have signal 2?

A

just co-stimulation = no effect

87
Q

what happens if you only have signal 1?

A

just p:MHC = anergy/hyporesponsive/inactivated/tolerance

MIMM 314 (23 decks)

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