Lecture 13 - Mechanisms in T Cell Activation (1) Flashcards
1
Q
what do lymphatics allow for?
A
allow for immunosurveillance
2
Q
what is immunosurveillance?
A
appropriate T cells are found in appropriate locations
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
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
5
Q
what is filtered from lymph when it goes thru LN?
A
LN filters ANTIGENS from the lymph
6
Q
why do the LN filter antigens from the lymph? (2)
A
- for recognition by T and B cells
- for destruction by macrophages to prevent spread
7
Q
2 routes for T cells to enter LN
A
- enters via blood thru HEV and stays in that LN
- enters via afferent lymphatics from another LN
8
Q
Afferent lymphatics
A
lymph flowing TOWARDS LN
9
Q
Efferent lymphatics
A
lymph flowing AWAY from LN
10
Q
how is directionality determined in lymphatics?
A
by 1-way valves
11
Q
what are the LFA adhesion molecule?
A
alpha and beta subunits of integrins
12
Q
what is the ligand for LFA/integrin?
A
ICAM from Ig superfamily
13
Q
structure of cells in the HEV
A
squamous endothelial cells
14
Q
4 general stages in leukocyte migration
A
- rolling
- activation
- adhesion
- diapedesis
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
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
17
Q
what allows endothelial cells in HEV to express adhesion molecules?
A
cytokines activate them
18
Q
what adhesion molecule mediates the first step of leukocyte migration: ROLLING?
A
L-selection aka CD62L
19
Q
what is the role of L-selection/CD62L?
A
to tether the T cell on the endothelium
20
Q
what adhesion molecule mediates the third step of leukocyte migration: ADHESION?
A
Integrins aka LFA-1
21
Q
what happens to the T cell during adhesion?
A
T cell loses its round shape and gets in tighter contact with HEV
22
Q
what occurs during DIAPEDESIS?
A
T cell migrates btwn endothelial cells
23
Q
speed of T cell during tethering
and speed of T cell during rolling
A
tethering: 4000 microns/sec
rolling: 40 microns/sec
24
Q
how long does leukocyte migration take?
A
10 min
25
what are naive T cells?
not activated/not exposed to antigen/in resting state
26
in general, what do naive T cells express?
homing receptors that binds SELECTINS or ADDRESSINS on endothelial cells in SLO
27
specifically, what does L-selectin/CD62L on naive T cells bind at the HEV
binds SLeX (carbohydrate) motif on CD34 and GlyCAM-1 on HEV
28
specifically, what does L-selectin/CD62L on naive T cells bind at the mucosal endothelium
binds SLeX on MAdCAM-1 on mucosal endothelium
29
what type of molecules are CD34 and GlyCAM-1?
addressin
30
do naive T cells express HIGH or LOW levels of CD62L? why?
HIGH levels of CD62L bc they need to be able to tether to HEV and reach LN
31
what happens to expression of CD62L once the T cells enter the LN?
upon entry to the LN, T cells meet an antigen and become activated and DOWNREGULATE expression of CD62L
32
why is CD62L downregulated in activated T cells?
so it can leave the LN and go to non-lymphoid tissues
33
what do CD62L levels indicate?
indicates which T cells have already seen their antigen or are about to see their antigen
34
what do integrins favour?
integrins favour cell adhesion to STABILIZE cell interactions
35
in the LN, how do T cells become activated?
T cell interacts with APC to meet its antigen
36
how does the T cell interact with APC?
ICAM-1 on APC binds LFA-1 on T cell
37
what is a unique feature of integrins/LFA-1?
must be activated!
38
describe process of activation of integrins/LFA-1 via TCR
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
2 ways that T cells become activated to increase affinity of integrin to LN
1. TCR
2. SLCs (CCL21/19)
40
3 molecules necessary for T cell entry into LN
1. Integrin/LFA-1
2. L-selection/CD62L
3. CCR7
41
describe the process of activation of integrins/LFA-1 via SLCs in HEV
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
what type of enzyme is involved in diapedesis?
proteases
43
what would happen if there was no chemokine signal to activate LFA-1?
LFA-1 would bind less strongly to ICAM-1 and T cells would not stop long enough for diapedesis
44
how was T cell homing discovered?
intravital microscopy
45
what type of receptor is CCR7 and other chemokine receptors?
GPCR
46
How does CCR7 expression change once T cells have seen their antigen? why?
CCR7 expression is downregulated bc once the cells have seen their antigen, want to encourage them to leave
47
what happens in B zones?
CXCL13 attracts Tfh and B cells via CXCR5
48
what happens in T zones?
T zones produce T cell and DC attracting chemokines, CCL19/21, to interact with CCR7
49
can peripheral tissues also recruit naive T cells?
yes
50
example of peripheral tissues that recruit naive T cells
lamina propria in the gut
51
describe the recruitment of naive T cells in lamina propria
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
purpose of anti-integrin therapies
target various alpha:beta integrins to affect cellular interactions, limiting movement and downstream activation
53
what pathway allows T cells to exit lymphoid organs?
sphingosine 1 phosphate (S1P)
54
what are S1P receptors?
GPCRs that target the lipid signaling molecule S1P
55
Describe the exit of T cells from the thymus and spleen with S1P pathway
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
Describe the exit of of T cells from the LN and peyer's patch with S1P pathway
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
what is FTY720 treatment?
inhibits egress of T cells from lymphoid organs as an immunosuppressant for MS treatment
57
why do we want to prevent egress in MS?
So T cells stay in LN and cannot leave to destroy the brain
58
relative expression of L-selectin in naive vs effector T cells
high in naive, absent in activated
59
relative expression of LFA-1 in naive vs effector T cells
present in naive, higher in activated
60
relative expression of CD44 in naive vs effector T cells
present in naive, higher in activated
61
what does CD44 bind?
CD44 binds hyaluronic acid in ECM
62
why is CD44 expressed more in activated T cells?
so they can bind well at inflammatory sites where ECM is
62
what is VLA?
Very Late Antigen
63
relative expression of VLA-4 in naive vs effector T cells
none in naive, lots in activated
64
why is there a lot of VLA-4 in activated T cells?
to allow homing of T cells to inflamed sites
65
overall role of adhesion molecules in naive T cells
so T cells can access lymphoid tissue for stimulation
66
overall role of adhesion molecules in memory T cells
so T cells can leave lymphoid organs and access sites of inflammation
67
what does location of T cell priming in the body determine?
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
T cell activation in skin-draining SLOs leads to:
T cell activation in skin-draining SLOs preferentially programs the upregulation of skin homing molecules
69
role of vitamin D
Vitamin D metabolites which are catalysed by sunlight may induce CCR10 expression
70
where do developmental cues come from after migrating to non-lymphoid tissues?
the tissue microenvironment
71
describe the circulation of T cells
active recirculation btwn blood, lymphoid, and non-lymphoid tissues
72
describe T cell scanning for T cell activation
in secondary lymphoid tissues, T cell scans for appropriate p:MHC that matches its TCR
73
what happens if the p:MHC does not match the TCR?
T cell will exit the LN and re-circulate to start over
74
what happens if the p:MHC does match the TCR?
T cell will stop
75
describe the experimental evidence of co-stimulation
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
what does it mean that condition 2 cannot activate T cells?
only has p:MHC signal so it cannot upregulate co-stimulatory molecules
77
what are the 2 signals involved in T cell activation?
Signal 1: Ag/TCR trigger
Signal 2: co-stimulation
78
what happens if a cell receives only signal 1?
T cell tolerance
79
when is T cell tolerance helpful?
to limit/block aberrant responses like autoimmunity
80
what costimulatory molecules does APC upregulate?
upregulates B7-1/CD80 and B7-2/CD86
81
what do B7 molecules bind?
B7 on APC bind constitutive CD28 on T cells
82
what type of molecules are B7 molecules and CD28 molecules?
Ig superfamily
83
4 ways that APCs can be activated to induce B7 expression
1. infection
2. stress
3. cellular damage
4. recognition by innate receptors
84
the ________ status of APC determines the signal
the activation status of APC determines the signal
85
are signal 1 and signal 2 sufficient alone?
NO --> they are each insufficient for T cell activation, need both
86
what happens if you only have signal 2?
just co-stimulation = no effect
87
what happens if you only have signal 1?
just p:MHC = anergy/hyporesponsive/inactivated/tolerance
