Lecture 18 - T Cell Differentiation Flashcards by Zara Jalil

what does maturity of SMAC depend on?

what occurs as SMAC matures?

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

cytoskeleton rearranges in fluid membrane to allow receptors to move

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

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

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What happens to Lck as SMAC matures?

Phosphorylated Lck that is important for signaling DECREASES

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What happens to ZAP70 as SMAC matures?

Phosphorylated ZAP that is important for signaling DECREASES

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

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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where are Lck and ZAP70 activated in the immunological synapse?

at the periphery, where TCR is at immature SMAC

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what are the 6 steps of TCR signaling?

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

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what are ITAMs?

immunoreceptor tyrosine-based activation motifs

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what is LAT?

scaffolding protein for other smaller proteins to bind and induce signaling

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what happens if downstream T cell signaling is messed up?

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

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

DCs: macropinocytosis, phagocytosis

Macrophages: phagocytosis

B cells: Ag specific receptor Ig

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

DCs: constitutive on mature DCs

Macrophages: inducible

B cells: inducible

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What does the maturation state of DC dictate?

dictates tolerance/immunity balance

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

functions:
- antigen uptake
- processing

location:
- in peripheral tissue

higher tolerance

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

functions:
- antigen presentation
- costimulation
- T cell activation

location:
- lymphoid tissue

higher immunity

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

express lots of adhesion molecules and IFN

anti-viral response!

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what is signal 3?

cytokines

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what is the role of signal 3?

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

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what cells produce the cytokines for signal 3?

APCs

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

innate-adaptive crosstalk
TLR activation
tolerogenic vs activating signals (LPS/TLR4 pathway)
T cell derived signals (CD40/CD40L)

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describe the original Th1/Th2 model

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

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what is a Th0 cell?

recently saw antigen but has not yet differentiated –> neutral

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what 2 cytokines cause Th0 –> Th1?

IL12 and IFN gamma

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general role of Th1 and 5 specific functions

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

what kind of pathogens does Th1 target?

intracellular pathogens

what 2 cytokines cause Th0 --> Th2

IL4 and IL2

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

HUMORAL IMMUNITY - can use Ab to block receptors and prevent pathogen from entering cell Acts on: 1. Mast cells 2. Eosinophils 3. Basophils

what type of pathogens does Th2 target?

extracellular parasites

2 types of immune responses that Th2 acts in

asthma and allergy

what 2 cytokines cause Th0 --> Th17?

TGFbeta and IL6

role of Th17 (3)?

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

what 2 cytokines cause Th0 --> Treg?

TGFbeta and IL12

2 types of Tregs?

1. Thymic Treg --> intrinsically suppressive 2. Peripheral Treg --> normal T cells converted to Treg

role of Tregs

modulation of immune responses and control pathology

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

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

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

TFs

2 TFs and 1 master TF for Th1 cytokines

Stat1, Stat4 Master: T-bet

2 TFs and 1 master TF for Th2 cytokines

Stat3, Stat6 Master: GATA3

1 TF and 1 master TF for Th17 cytokines

Stat3 Master: RORyt

master TF for Treg

FoxP3

What happens if you block IL12?

Blocks Th1 lineage --> cannot combat mycobacterial infections

how does polarizing cytokine of 1 lineage affect other lineages?

polarizing cytokine of 1 lineage ANTAGONIZES other lineages

2 cytokines produced by Treg

1. TGFbeta 2. IL10

2 cytokines produced by Th17

1. IL6 2. IL17

2 cytokines produced by Th1

1. IL2 2. IFNy

2 cytokines produced by Th2

1. IL4 2. IL5

2 cytokines produced by Tr1/Th3

1. IL10 2. TGFbeta

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

1. Th17 2. Th1 3. Th2

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

1. Treg 2. Tr1/Th3

role of IL23

not polarizing, so it is required for Th17 survival

what happens to mice with IL23 deficiency ?

Th17 cells don't work

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

Target IL23 --> block Th17 survival

does IL23-targeted therapy block Th17 development? why?

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

which 2 T cells use TGFbeta as polarizing cytokine?

Treg and Th17

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

Th17 requires IL6 in addition to TGFbeta

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

both produce TGFbeta and IL10 as suppressive/tolerance cytokines

role of Tr1/Th3 cells

allow tolerance to food antigens in the gut

why can T cells have different differentiation pathways

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

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

1. Th9 2. Th22

what is the role of Th9?

allergy and autoimmunity against melanoma and intestinal worms

what is the main cytokine that induces Th9 differentiation?

IL2

which 2 cytokines enhance Th9 differentiation?

1. TGFbeta 2. IL4

Which 2 TFs control Th9 development?

1. IRF4 2. PU.1

what is the role of Th22?

gut antibacterial defence

is Th17 or Th22 more effective at gut antibacterial defense?

Th22

what cytokine controls Th22 development?

IL6 (in absence of TGFbeta)

which 2 TFs control Th22 development?

1. Tbet 2. AhR

What cytokine do Th22 cells make?

IL22

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

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

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

1. TFs can better access promoters 2. epigenetic modifications

4 instrinsic mechanisms of T cell plasticity

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

2 extrinsic mechanisms of T cell plasticity

1. interactionswith innate receptors 2. cytokine receptors on T cells

what type of protein regulates cytokine responses?

Suppressor of Cytokine Signaling (SOCS)

what induces SOCS?

Cytokines

role of SOCS?

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

SOCS3 overexpression

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

SOCS3 deletion

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

SOCS1 deletion

There is increaed Treg but with impaired function

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

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

what cells are the best APC activators

Th1

2 signals from Th1 to activate APC

1. CD40L sensitizes APC 2. secretion of IFNy

why are Th2 cells ineffective at activating APC?

Th2 produce IL10 which deactivates macrophages

how does IL10 deactivate macrophages?

suppressing B7 costimulation

what do activated APCs secrete?

TNFalpha

what type of cytokine is TNFalpha?

autocrine activator

2 roles of TNFalpha for activated APC

1. activate intracellular killing mechainsms 2. increased Ag presentation

what happens to APC if you block TNFalpha?

inhibits APC activation

how does Th1 allow for killing extracellular pathogens and tissues?

release toxic compounds

3 toxic compounds released by Th1?

1. ROS and NO 2. Proteases 3. Antimicrobial peptides

6 general roles of Th1

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

how do Th2 and Tfh cells help humoral immunity?

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

why is the nature of the pathogen important?

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

describe type of response for virus and tumour pathogens

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

describe type of response for microbes that infect macrophage vesicles

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

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

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

describe cytokine-mediated bystander CD8 T cells

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

role of CD8 CTL

Cause antigen-specific apoptosis

role of adhesion molecules in CTL-mediated killing?

allow more efficient binding to potential targets

describe the interactions btwn CTL and cells

transient unless Ag is encountered