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MIMM 314 > Lecture 17 - Mechanisms in T Cell Activation (2) > Flashcards

Lecture 17 - Mechanisms in T Cell Activation (2) Flashcards

1
Q

what is productive T cell activation?

A

antigen recognition causes signaling event that allows cell to respond (growth, cytokine production)

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2
Q

what allows for productive T cell activation?

A

signals 1 and 2

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3
Q

where is CD4 located?

A

located intracellularly near T cell surface

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4
Q

what does CD4 do?

A

it is intracellularly bound to kinase that activates signaling once p:MHC interacts with TCR

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5
Q

what allows for maximal T cell activation?

A

signal 1 and 2 must be STRONG

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6
Q

what cell is CD40 expressed on?

A

APC

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7
Q

what cell is CD40L expressed on?

A

T cell

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8
Q

describe the expression of CD40/CD40L

A

INDUCIBLE

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9
Q

what induces CD40/CD40L expression?

A

signal 1

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10
Q

role of CD40/CD40L interaction

A

CD40 and CD40L bind upon TCR interaction and further upregulate B7.1/B7.2 to prime APC for signal 2

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11
Q

what does signal 2 allow for?

A

helps with fine-tuning to meet requirements of diff T cells

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12
Q

describe T cell response due to NONBACTERIAL PROTEIN ANTIGEN

A

APC presents the nonbacterial antigen

T cell recognizes peptide via signal 1 but since it is nonbacterial, there is no TLR signaling and no signal 2 –> ANERGY

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13
Q

Example of nonbacterial protein antigen

A

self-antigen

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13
Q

describe T cell response due to BACTERIAL ANTIGEN

A

APC presents the bacterial antigen

T cell recognizes peptide via signal 1, then signal 2 can occur bc of bacterial stimulation of TLR –> T cell activation and expansion

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13
Q

describe T cell response due to BACTERIA AND NONBACTERIAL ANTIGEN

what can this lead to?

A

APC exposed to combo of bacteria and nonbacterial antigen

Presence of bacteria can induce B7 allowing signal 2 to occur for T cell to recognize the nonbacterial antigen –> makes T cells that are specific for the nonbacterial antigen

leads to autoimmunity

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14
Q

when are cases of autoimmunity more common? why?

A

after viral epidemic/outbreak in a community

pathogenic antigen allows signal 2 to make T cells self-reactive

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15
Q

how does our body avoid autoimmunity/self-reactivity?

A

prevent signal 2 aka prevent upregulation of B7 and induce anergy

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16
Q

describe induction of CD40/CD40L

A

induced by signal 1 and further upregulated by presence of bacterial antigen

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17
Q

what happens in CD40L-/- mice? what does this indicate?

A

CD40L-/- mice have short and weak clonal expansion in response to antigen

indicates that activation of APC thru CD40 is important for T cell activation

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18
Q

what does ICOS stand for?

A

Inducible co-stimulator

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19
Q

3 important roles of ICOS

A
  1. germinal center development
  2. class switching
  3. Th2 cell response
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20
Q

ICOS is similar to:

A

ICOS is structurally similar to CD28

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21
Q

When is ICOS induced?

A

ICOS is inducible on recently activated T cells

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22
Q

what does ICOS bind? on which cells?

A

ICOS on activated T cells interact with ICOS-L on activated APC

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23
reminder: what allows APC to be activated?
TLR signaling
24
what does ICOS/ICOS-L interaction stimulate?
stimulates production of IL10 --> Th2 cytokine
25
describe the bidirectional signaling btwn T cells and APC
APCs activate T cells T cells also allow for further APC maturation which then will further help the T cell
26
what is the "master" cell surface molecule?
CD28
27
Why is CD28 the "master" cell surface molecule?
upon TCR stimulation induces other co-stimulatory receptors from Ig and TNFR/TNFL superfamilies
28
what happens if CD28 and B7 are removed?
other co-stimulatory receptors cannot be induced --> no more downstream pathways and T cells become anergic
29
describe T cells in tumour or viral infection
CD4+ T cell strengthens CD8+ T cell
30
role of CD8 T cells
cytolytic --> kill tumour cells and virus-infected cells
31
describe how CD4+ T cells help CD8+ T cells (4)
1. APC stimulates CD4+ T cell 2. activated CD4+ T cell activates the APC 3. activated APC expresses CD40 and 4-IBBL 4. CD40 and 4-IBBL act as co-stimulatory molecules for the naive CD8+ T cell
32
how does T cell license the APC?
Express CD40 and 4-IBBL
33
in addition to co-stimulatory molecules, what must the APC express to be able to be licensed by CD4 and activate CD8?
MHC I and MHC II
34
what does CD4 produce to help CD8 expansion?
CD4 produces IL2
35
In summary: what 2 things are responsible for the activation of extra strong CD8 function?
1. surface receptors 2. IL2
36
How does CD4 licensing APC occur in self-reactivity?
can occur when antigen is presented in presence of infection
37
describe the downstream pathway induced by CD28 leading to T cell activation (4)
1. TCR/CD8 costimulation activates IkB (IKK) complex 2. IKK phosphorylates IkB leading to release of c-Rel subunits from NfkB 3. c-Rel moves to nucleus to allow transcription of IL2 4. IL2 acts in autocrine to IL2R on same cell for T cell activation and proliferation
38
describe the downstream pathway induced by CD28 leading to T cell anergy (5)
1. TCR/CD28 costimulation activates IkB (IKK) complex and Peli1 2. IKK phosphorylates IkB leading to release of c-Rel subunits from NfkB 3. Peli1 ubiquitinates c-Rel 4. c-Rel is targeted to proteasome for degradation 5. T cell becomes anergic
39
what type of enzyme is Peli1?
U3 ubiquitin ligase
40
when is Peli1 inducible? (2)
1. in cells that have been chronically activated to DOWNREGULATE response 2. in cells where signal 2 is not optimal
41
therefore, what is important regulator in CD28 activity?
Peli1
42
structure of IL2R
3 subunits: alpha, gamma, beta
43
describe IL2R gamma subunit
common gamma chain --> intracellular, primary signaling chain
44
describe IL2R beta subunit
half is intracellular, half is extracellular does some signaling and some binding to IL2
45
describe IL2R alpha subunit
ONLY IN ACTIVATED T CELL when there are high levels of IL2 produced upon T cell activation mainly extracellular and binds IL2 to bring IL2 to beta and gamma subunits
46
does IL2 act autocrine, paracrine, or endocrine?
autocrine and paracrine
47
2 examples of IL2 as therapeutic target
1. cyclosporin A 2. Rapmycin
48
what is cyclosporin A? when is it used?
calcineurin (NFAT) inhibitor to block IL2 production used in transplants to wipe out T cells
49
what is Rapamycin? when is it used (2)?
mTOR to block IL2R signaling used in transplants and autoimmunity
50
why must T cells be dividing/proliferating to allow differentiation?
during division, DNA is more open and accessible so gene expression can be more easily altered
51
what molecules turns T cells OFF?
CTLA-4
52
how does CTLA-4 turn off T cell activation?
binds B7 with 20x higher affinity than CD28 as T cell activation occurs, CTLA4 is upregulated and T cell gets progressively more inactivated as CTLA4 competes with CD28 for B7 binding
53
what happens in CTLA4 deficient mice?
massive lymphocyte proliferation --> lethal!
54
4 example of signaling pathways that can be activated by CD28
1. Ras 2. PKC 3. AKT 4. PLCgamma
55
pathway activated by ICOS (4 steps)
1. ICOS activates PI3K 2. recruits more active form of PI3K subunit p50alpha 3. allows better/more efficient AKT signaling to allow downstream activation of C-MAF TF 4. produces IL4 and IL10
56
what enzymes are activated to turn T cells ON?
kinases
57
what enzymes are activated to turn T cells OFF?
phosphatase
58
what are 3 receptors that activate phosphatase activity?
1. BTLA4 2. PD1 3. CTLA4
59
3 examples of phosphatases that turn off T cell activation?
1. SHP1 2. SHP2 3. PP2A
60
What is the interaction btwn APC and T cells called?
Super Molecular Activating Complex (SMAC)
61
What are the 3 type of interactions that make up SMAC?
1. Co-stimulatory 2. TCR-MHC 3. Adhesion
62
what does SMAC allow for?
SMAC dictates Ag recognition and productive T cell activation
63
describe SMAC within minutes on APC-T cell interaction and what is it called?
ICAM1/LFA1 are at the core of the interaction, with TCR/MHC on the outside Immature/peripheral SMAC
64
describe SMAC after hours of APC-T cell interaction and what is it called?
TCR/MHC are at the core of the interaction, with ICAM1/LFA on the outside mature/central SMAC

MIMM 314 (23 decks)

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