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MIMM 314 > Lecture 18 - T Cell Differentiation > Flashcards

Lecture 18 - T Cell Differentiation Flashcards

1
Q

what does maturity of SMAC depend on?

what occurs as SMAC matures?

A

time!

TCR/MHC moves to center and LFA/ICAM moves to periphery of SMAC for stronger interaction btwn APC and T cell

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2
Q

what allows for the movement of receptors on APC and T cell to form mature SMAC?

A

cytoskeleton rearranges in fluid membrane to allow receptors to move

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3
Q

how can we determine if the reshuffling of receptors on cell surface is important?

A

determine if the activation of TCR leads to downstream signaling via Lck and ZAP70

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4
Q

What happens to Lck as SMAC matures?

A

Phosphorylated Lck that is important for signaling DECREASES

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5
Q

What happens to ZAP70 as SMAC matures?

A

Phosphorylated ZAP that is important for signaling DECREASES

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6
Q

What can we conclude from the fact that phosphorylated Lck and ZAP70 decrease as SMAC matures?

A

T cell signaling begins before immunological synapse / mature SMAC forms –> therefore immunological synapse / mature SMAC is not required to initiate T cell activation

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7
Q

where are Lck and ZAP70 activated in the immunological synapse?

A

at the periphery, where TCR is at immature SMAC

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8
Q

what are the 6 steps of TCR signaling?

A
  1. TCR-MHC interaction + CD4 and CD28 co-receptors recruit Lck
  2. Lck phosphorylates CD3 at ITAMs
  3. ZAP70 binds double-phosphorylated ITAM residues
  4. ZAP70 is phosphorylated and activated by Lck
  5. LAT is recruited and phosphorylated ZAP70 at many tyrosine residues on C-terminal tail
  6. many signaling adaptors and effectors assemble to form large signaling network
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9
Q

what are ITAMs?

A

immunoreceptor tyrosine-based activation motifs

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10
Q

what is LAT?

A

scaffolding protein for other smaller proteins to bind and induce signaling

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11
Q

what happens if downstream T cell signaling is messed up?

A

cannot sufficiently activate T cells –> no specific T cell development

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12
Q

how do DCs vs macrophages vs B cells take up antigens?

A

DCs: macropinocytosis, phagocytosis

Macrophages: phagocytosis

B cells: Ag specific receptor Ig

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13
Q

how do DCs vs macrophages vs B cells deliver co-stimulation signals?

A

DCs: constitutive on mature DCs

Macrophages: inducible

B cells: inducible

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14
Q

What does the maturation state of DC dictate?

A

dictates tolerance/immunity balance

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15
Q

immature DC
- functions (2)
- location
- level of tolerance vs immunity

A

functions:
- antigen uptake
- processing

location:
- in peripheral tissue

higher tolerance

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16
Q

mature DC
- functions (3)
- location
- level of tolerance vs immunity

A

functions:
- antigen presentation
- costimulation
- T cell activation

location:
- lymphoid tissue

higher immunity

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17
Q

what do plasmacytoid dendritic cells express? how does this affect their function?

A

express lots of adhesion molecules and IFN

anti-viral response!

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18
Q

what is signal 3?

A

cytokines

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19
Q

what is the role of signal 3?

A

gives specialized function to T cell for differentiation and influences the type of immune response

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20
Q

what cells produce the cytokines for signal 3?

A

APCs

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21
Q

4 ways that APCs can get activated to make cytokines for signal 3

A
  1. innate-adaptive crosstalk
  2. TLR activation
  3. tolerogenic vs activating signals (LPS/TLR4 pathway)
  4. T cell derived signals (CD40/CD40L)
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22
Q

describe the original Th1/Th2 model

A

cytokines from signal 3 determine whether a T cell induces cell-mediated or humoral immunity

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23
Q

what is a Th0 cell?

A

recently saw antigen but has not yet differentiated –> neutral

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24
Q

what 2 cytokines cause Th0 –> Th1?

A

IL12 and IFN gamma

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25
Q

general role of Th1 and 5 specific functions

A

CELL-MEDIATED IMMUNITY
1. Autoimmunity
2. Inflammation
3. CTL, DTH
4. Allow production of opsonizing IgG
5. APC activation

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26
Q

what kind of pathogens does Th1 target?

A

intracellular pathogens

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27
Q

what 2 cytokines cause Th0 –> Th2

A

IL4 and IL2

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28
Q

general role of Th2, an example of a function, and 3 cells it acts on

A

HUMORAL IMMUNITY
- can use Ab to block receptors and prevent pathogen from entering cell

Acts on:
1. Mast cells
2. Eosinophils
3. Basophils

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29
Q

what type of pathogens does Th2 target?

A

extracellular parasites

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30
Q

2 types of immune responses that Th2 acts in

A

asthma and allergy

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31
Q

what 2 cytokines cause Th0 –> Th17?

A

TGFbeta and IL6

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32
Q

role of Th17 (3)?

A
  1. Targets extracellular bacteria at barrier sites
  2. Fungi
  3. Autoimmunity
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33
Q

what 2 cytokines cause Th0 –> Treg?

A

TGFbeta and IL12

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34
Q

2 types of Tregs?

A
  1. Thymic Treg –> intrinsically suppressive
  2. Peripheral Treg –> normal T cells converted to Treg
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35
Q

role of Tregs

A

modulation of immune responses and control pathology

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36
Q

what is the only thing required for naive T cell to differentiate

A

cytokines! a naive T cell can have same TCR, antigen-specificity, etc but can differentiate into multiple lineages based on cytokine environment

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37
Q

what do cytokines rely on to be produced in specific T cells?

A

TFs

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38
Q

2 TFs and 1 master TF for Th1 cytokines

A

Stat1, Stat4

Master: T-bet

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39
Q

2 TFs and 1 master TF for Th2 cytokines

A

Stat3, Stat6

Master: GATA3

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40
Q

1 TF and 1 master TF for Th17 cytokines

A

Stat3

Master: RORyt

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41
Q

master TF for Treg

A

FoxP3

42
Q

What happens if you block IL12?

A

Blocks Th1 lineage –> cannot combat mycobacterial infections

43
Q

how does polarizing cytokine of 1 lineage affect other lineages?

A

polarizing cytokine of 1 lineage ANTAGONIZES other lineages

44
Q

2 cytokines produced by Treg

A
  1. TGFbeta
  2. IL10
45
Q

2 cytokines produced by Th17

A
  1. IL6
  2. IL17
46
Q

2 cytokines produced by Th1

A
  1. IL2
  2. IFNy
47
Q

2 cytokines produced by Th2

A
  1. IL4
  2. IL5
48
Q

2 cytokines produced by Tr1/Th3

A
  1. IL10
  2. TGFbeta
49
Q

which 3 types of effector T cells are involved in immunity?

A
  1. Th17
  2. Th1
  3. Th2
50
Q

which 2 types of effector T cells are involved in suppression / tolerance

A
  1. Treg
  2. Tr1/Th3
51
Q

role of IL23

A

not polarizing, so it is required for Th17 survival

52
Q

what happens to mice with IL23 deficiency ?

A

Th17 cells don’t work

53
Q

if IBD is driven by Th17 cells, what is a therapy we can use to help IBD?

A

Target IL23 –> block Th17 survival

54
Q

does IL23-targeted therapy block Th17 development? why?

A

no –> IL23 is not a polarizing cytokine so it doesn’t affect development, just survival

55
Q

which 2 T cells use TGFbeta as polarizing cytokine?

A

Treg and Th17

56
Q

if TGFbeta is used as polarizing cytokine for Treg and Th17, how do they have diff function?

A

Th17 requires IL6 in addition to TGFbeta

57
Q

what do Treg and Tr1/Th3 cells have in common?

A

both produce TGFbeta and IL10 as suppressive/tolerance cytokines

58
Q

role of Tr1/Th3 cells

A

allow tolerance to food antigens in the gut

59
Q

why can T cells have different differentiation pathways

A

T cells have plasticity –> can shift chromatin remodelling to affect gene programing and alter which genes get activated

60
Q

what are the 2 newer types of T cells that have been discovered?

A
  1. Th9
  2. Th22
61
Q

what is the role of Th9?

A

allergy and autoimmunity against melanoma and intestinal worms

62
Q

what is the main cytokine that induces Th9 differentiation?

A

IL2

63
Q

which 2 cytokines enhance Th9 differentiation?

A
  1. TGFbeta
  2. IL4
64
Q

Which 2 TFs control Th9 development?

A
  1. IRF4
  2. PU.1
65
Q

what is the role of Th22?

A

gut antibacterial defence

66
Q

is Th17 or Th22 more effective at gut antibacterial defense?

A

Th22

67
Q

what cytokine controls Th22 development?

A

IL6 (in absence of TGFbeta)

68
Q

which 2 TFs control Th22 development?

A
  1. Tbet
  2. AhR
69
Q

What cytokine do Th22 cells make?

A

IL22

70
Q

What is the advantage of having many different effector T cell types?

A

can have stronger, better, customized, adapted responses to diff antigens –> T cell in 1 microenvironment causes diff response than T cell in another microenvironment

71
Q

how does opening of chromatin help T cell differentiation? (2)

A
  1. TFs can better access promoters
  2. epigenetic modifications
72
Q

4 instrinsic mechanisms of T cell plasticity

A
  1. earlier in cell maturation/more naive = more plasticity
  2. miRNAs can post-transcriptionally alter T cell
  3. Epigenetic marks can change TF expression and activation
  4. Change in nutrient availability can affect metabolic pathways and alter T cell function
73
Q

2 extrinsic mechanisms of T cell plasticity

A
  1. interactionswith innate receptors
  2. cytokine receptors on T cells
74
Q

what type of protein regulates cytokine responses?

A

Suppressor of Cytokine Signaling (SOCS)

75
Q

what induces SOCS?

A

Cytokines

76
Q

role of SOCS?

A

Act downstream of cytokine receptors, causing negative feedback loop to attenuate cytokine signaling, only allowing a specific type of Th cell to produce cytokines

77
Q

SOCS3 overexpression

A

Th1 is INHIBITED by suppressing IL12-mediated STAT4 activation so there is increased Th2

78
Q

SOCS3 deletion

A

Th1 is INHIBITED by promoting production of IL10 and TGFbeta so there is increased Th17

79
Q

SOCS1 deletion

A

There is increaed Treg but with impaired function

80
Q

are cytokines produced by Th cells unique to a specific lineage?

A

some cytokines are only involved in 1 lineage, others are involved in many lineages

81
Q

what cells are the best APC activators

A

Th1

82
Q

2 signals from Th1 to activate APC

A
  1. CD40L sensitizes APC
  2. secretion of IFNy
83
Q

why are Th2 cells ineffective at activating APC?

A

Th2 produce IL10 which deactivates macrophages

84
Q

how does IL10 deactivate macrophages?

A

suppressing B7 costimulation

85
Q

what do activated APCs secrete?

A

TNFalpha

86
Q

what type of cytokine is TNFalpha?

A

autocrine activator

87
Q

2 roles of TNFalpha for activated APC

A
  1. activate intracellular killing mechainsms
  2. increased Ag presentation
88
Q

what happens to APC if you block TNFalpha?

A

inhibits APC activation

89
Q

how does Th1 allow for killing extracellular pathogens and tissues?

A

release toxic compounds

90
Q

3 toxic compounds released by Th1?

A
  1. ROS and NO
  2. Proteases
  3. Antimicrobial peptides
91
Q

6 general roles of Th1

A
  1. activates macrophages
  2. kills chronically infected cells
  3. induces T cell proliferation
  4. induces macrophage differentiation
  5. activate endothelium to allow macrophage exit from circulation to site of infection
  6. causes macrophages to accumulate at site of infection
92
Q

how do Th2 and Tfh cells help humoral immunity?

A

Th2 and Tfh make IL4 which regulates Th2/Tfh B cell interactions in germinal center to allow Ab production

93
Q

why is the nature of the pathogen important?

A

where/how it infects will drive T cell differentiation and the outcome of immunity

94
Q

describe type of response for virus and tumour pathogens

A

cytosolic pathogens –> activate CD8 T cells –> recognize p:MHC I on infected cell –> kill infected cell

95
Q

describe type of response for microbes that infect macrophage vesicles

A

activate Th1 cells –> recognize p:MHC II on infected macrophage –> activate infected macrophage

96
Q

describe type of response for microbes that are found in extracellular fluid

A

activate Th1 or Th2 (but preferentially Th2) –> recognize p:MHC II on Ag-specific B cell –> activate B cell to make Ab

97
Q

describe cytokine-mediated bystander CD8 T cells

A

activated DC can induce bystander naive CD8 T cells to produce IFNy and promote resistance to microbes

98
Q

role of CD8 CTL

A

Cause antigen-specific apoptosis

99
Q

role of adhesion molecules in CTL-mediated killing?

A

allow more efficient binding to potential targets

100
Q

describe the interactions btwn CTL and cells

A

transient unless Ag is encountered

MIMM 314 (23 decks)

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