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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
Q

reminder: what allows APC to be activated?

A

TLR signaling

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24
Q

what does ICOS/ICOS-L interaction stimulate?

A

stimulates production of IL10 –> Th2 cytokine

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25
Q

describe the bidirectional signaling btwn T cells and APC

A

APCs activate T cells

T cells also allow for further APC maturation which then will further help the T cell

26
Q

what is the “master” cell surface molecule?

A

CD28

27
Q

Why is CD28 the “master” cell surface molecule?

A

upon TCR stimulation induces other co-stimulatory receptors from Ig and TNFR/TNFL superfamilies

28
Q

what happens if CD28 and B7 are removed?

A

other co-stimulatory receptors cannot be induced –> no more downstream pathways and T cells become anergic

29
Q

describe T cells in tumour or viral infection

A

CD4+ T cell strengthens CD8+ T cell

30
Q

role of CD8 T cells

A

cytolytic –> kill tumour cells and virus-infected cells

31
Q

describe how CD4+ T cells help CD8+ T cells (4)

A
  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
Q

how does T cell license the APC?

A

Express CD40 and 4-IBBL

33
Q

in addition to co-stimulatory molecules, what must the APC express to be able to be licensed by CD4 and activate CD8?

A

MHC I and MHC II

34
Q

what does CD4 produce to help CD8 expansion?

A

CD4 produces IL2

35
Q

In summary: what 2 things are responsible for the activation of extra strong CD8 function?

A
  1. surface receptors
  2. IL2
36
Q

How does CD4 licensing APC occur in self-reactivity?

A

can occur when antigen is presented in presence of infection

37
Q

describe the downstream pathway induced by CD28 leading to T cell activation (4)

A
  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
Q

describe the downstream pathway induced by CD28 leading to T cell anergy (5)

A
  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
Q

what type of enzyme is Peli1?

A

U3 ubiquitin ligase

40
Q

when is Peli1 inducible? (2)

A
  1. in cells that have been chronically activated to DOWNREGULATE response
  2. in cells where signal 2 is not optimal
41
Q

therefore, what is important regulator in CD28 activity?

A

Peli1

42
Q

structure of IL2R

A

3 subunits: alpha, gamma, beta

43
Q

describe IL2R gamma subunit

A

common gamma chain –> intracellular, primary signaling chain

44
Q

describe IL2R beta subunit

A

half is intracellular, half is extracellular

does some signaling and some binding to IL2

45
Q

describe IL2R alpha subunit

A

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
Q

does IL2 act autocrine, paracrine, or endocrine?

A

autocrine and paracrine

47
Q

2 examples of IL2 as therapeutic target

A
  1. cyclosporin A
  2. Rapmycin
48
Q

what is cyclosporin A?

when is it used?

A

calcineurin (NFAT) inhibitor to block IL2 production

used in transplants to wipe out T cells

49
Q

what is Rapamycin?

when is it used (2)?

A

mTOR to block IL2R signaling

used in transplants and autoimmunity

50
Q

why must T cells be dividing/proliferating to allow differentiation?

A

during division, DNA is more open and accessible so gene expression can be more easily altered

51
Q

what molecules turns T cells OFF?

A

CTLA-4

52
Q

how does CTLA-4 turn off T cell activation?

A

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
Q

what happens in CTLA4 deficient mice?

A

massive lymphocyte proliferation –> lethal!

54
Q

4 example of signaling pathways that can be activated by CD28

A
  1. Ras
  2. PKC
  3. AKT
  4. PLCgamma
55
Q

pathway activated by ICOS (4 steps)

A
  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
Q

what enzymes are activated to turn T cells ON?

A

kinases

57
Q

what enzymes are activated to turn T cells OFF?

A

phosphatase

58
Q

what are 3 receptors that activate phosphatase activity?

A
  1. BTLA4
  2. PD1
  3. CTLA4
59
Q

3 examples of phosphatases that turn off T cell activation?

A
  1. SHP1
  2. SHP2
  3. PP2A
60
Q

What is the interaction btwn APC and T cells called?

A

Super Molecular Activating Complex (SMAC)

61
Q

What are the 3 type of interactions that make up SMAC?

A
  1. Co-stimulatory
  2. TCR-MHC
  3. Adhesion
62
Q

what does SMAC allow for?

A

SMAC dictates Ag recognition and productive T cell activation

63
Q

describe SMAC within minutes on APC-T cell interaction and what is it called?

A

ICAM1/LFA1 are at the core of the interaction, with TCR/MHC on the outside

Immature/peripheral SMAC

64
Q

describe SMAC after hours of APC-T cell interaction and what is it called?

A

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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