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MICR334 - Advanced Immunology > MODULE 2 - ROS KEMP'S LECTURES > Flashcards

MODULE 2 - ROS KEMP'S LECTURES Flashcards

1
Q

what are some things effector T cells do?

A

move to different places in the body

kill infected cells (in different ways)

support antibody production

enhance innate immune system by enhances bacterial killing

make different types of cytokines

remember the antigen for next time

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2
Q

why are different effector responses needed to fight different pathogens?

A

different types of organisms

different routes of infection

different site of infection

different molecules etc.

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3
Q

what are the main subsets of CD4+ T cells?

A

mainly:

Th1

Th2

Th3

Th17

Treg

also:

T follicular helper

Th9

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4
Q

how do cytokines lead to different effector functions?

A

APCs produce cytokines

cytokines activate T cells

T cells produce cytokines (could be more or the same or different kinds). These go off and act on immune cells including T cells

cytokines act on T cell to initiate downstream functions e.g. more cytokines, killing enzymes, chemokine, metabolic products, survival proteins etc.

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5
Q

what immune cells do cytokines act on?

A

phagocytes

T cells

B cells

non-immune cells

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6
Q

what are polarising cytokines?

A

produced by other immune cells (not T cells) (usually innate cells such as APCs)

bind to receptors on naive T cell surface

help drive differentiation into different T cell subsets

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7
Q

what are effector cytokines?

A

produced by different T cell subsets

bind to receptors on other cells

leads to effector functions in other cells and are usually suited for whatever pathogen initiated the response

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8
Q

outline the process of polarising cytokine acting on naive T cell leading to Th1 effector functions?

A

APC produces IL-12 based off of signals it receives

IL-12 receptor (dimer) on T cell picks this up leading to activation of T-bet transcription factor resulting in production of IFN-gamma

IFN-gamma acts on macrophages to increase phagocytosis/enhance bacterial killing, acts on CD8 T cells to kill infected cells and acts on B cells to make/improve antibody to enhance phagocytosis

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9
Q

what type of infection is IFN-gamma effector cytokine most useful for?

A

intracellular infections (virus, bacteria)

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10
Q

outline the process of polarising cytokines acting on naive T cell leading to Th2 effector functions?

A

APC produces IL-4 which is received by IL-4 receptor

this leads to activation of GATA-3 transcription factor leading to production of cytokines such as IL-4, IL-5 and IL-13 which are very good for extracellular infections such as worms and parasites

these effector cytokines promote mast cell eosinophils to destroy worms, tell CD4 T cells to produce more IL-4, 5 and 13 and tell B cells to make antibody to bind pathogens

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11
Q

outline the process of polarising cytokines acting on naive T cell leading to Th17 effector functions?

A

APC produces TGF-beta and IL-6 which go and act on their given receptors on the naive T cell

these polarising cytokines act on ROR-gammaT transcription factor leading to production of IL-17 which causes neutrophils to cause inflammation. Also tells T cells to produce IL-22 which is causes a positive feedback loop for Th17

Th17 is a pro-inflammatory cell as IL-17 causes inflammation

Also responsible for most autoimmune inflammatory diseases such as MS and IBD

generally good for extracellular infections such as fungus and bacteria

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12
Q

is it just CD4 T cells that have subsets?

A

No!

So do CD8+ T cells and they are similar to CD4+ subsets

Tc1, Tc2, Tc17

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13
Q

are T cell subsets mutually exclusive?

A

nah we just learn it like that cause we aren’t fucking smart enough

T cells can low-key maybe display more than one effector phenotype and change from one phenotype to another

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14
Q

different effector strategies are important for dealing with different pathogens, but what can uncontrolled effector responses lead to?

A

immunopathologies

different subsets associated with different pathologies

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15
Q

how can Th1 cells contribute to autoimmune diseases?

A

they secrete IFN-gamma which is pro-inflammatory. This is good for activating cell mediated immunity e.g. killing infected and cancer cells but

IFN-gamma activates inflammatory mediators and other cells. IFN-gamma receptor on many cells in body, this can result in tissue damage. IFN-gamma also promotes antibody class switching to IgG which is a more potent antibody i.e. more damage

this contributes to autoimmune diseases such as lupus and type I diabetes

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16
Q

how does Th2 contribute to allergy?

A

Th2 secretes IL-4, IL-5 and IL-13 which help clear parasites by stimulating mucus production, smooth muscle contraction and antibody class switching to IgE

however this contributes to respiratory issues cause smooth muscle contraction and excess mucus production is fucked if its in the respiratory tract (asthma)

IgE binds to mast cells and basophils leading to activation of macrophages in lungs, degranulation, release of pro inflammatory modulators and allergic inflammation

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17
Q

how can Th17 contribute to autoimmune disease?

A

Th17 secretes IL-17 which is good for immunity to extracellular bacteria such as Klebsiella pneumoneae. It recruits and activates neutrophils which are essential for Klebsiella clearance. Also involved in tissue immunity in the gut, skin, lints however can be associated with tissue specific AI disease e.g. IBD

IL-17 is a pro-inflammatory cytokine and IL-17 receptors are present on epithelial tissues. It also promotes production of enzymes that can cause tissue damage

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18
Q

generally outline the process of signal transduction?

A

extracellular molecule activates a cell surface molecule (receptor)

this receptor alters intracellular molecules

amplification of the signal

ultimately you get gene transcription and protein production

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19
Q

what are the first messengers of signal transduction?

A

natural inter-cellular ligands that bind and activate receptors e.g. cytokines

need receptors in the membrane

a bit different in the case of TCR as it is not the thing activating it as MHC is

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20
Q

what are the second messengers of signal transduction?

A

enter the cytoplasm and trigger response within the cell

chemical relays from plasma membrane to cytoplasm

intracellular signal transduction

tend to just be a shit load of proteins in the cell

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21
Q

what are membrane receptors in signal transduction?

A

external influences determine what happens inside target cell

cell membrane impermeable to influences, so receptors in the membrane allow molecules to get through

these are needed for signal transduction to occur

basically takes signal from outside cell inside cell e.g. TCR

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22
Q

what is affinity?

A

strength of binding (e.g. of interaction between MHC and TCR)

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23
Q

what is avidity?

A

total strength of interaction (e.g. total impact of everything binding like the interaction between a T cell and an APC with all the MHC-TCR interactions and other ligands together)

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24
Q

what is a way of stopping signal transduction?

A

down regulating a receptor

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25
Q

outline the TCR structure?

A

two chains - alpha and beta

variable region and constant region

membrane bound only (unlike BCR)

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26
Q

what part of the TCR binds antigen and MHC?

A

the variable region

although this and the constant region of the TCR have no signalling capacity

the signalling comes from the CD3 molecules around it which have the capacity to transmit a signal and join up with the TCR to form the TCR complex

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27
Q

outline the molecules/interactions involved in T cell activation?

A

TCR-MHC (signal 1) - antigen-specific

CD4/CD8-MHC - co-receptor

LFA1-ICAM - adhesion

CD28-CD80 (signal 2) - co-stimulation

APC-IL-12 - inflammatory signals

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28
Q

what occurs during the antigen-specific interaction between TCR and MHC (signal 1)?

A

T cell recognises specific antigen in the context of MHC

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29
Q

what occurs during the interaction between CD4/CD8 co-receptors and MHC?

A

CD4-MHCII

CD8-MHCI

co-receptors stabilise low-affinity interaction between the TCR and MHC keeping the cells together by stabilising cell-cell binding

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30
Q

what occurs during the interaction between adhesion molecules LFA-1 and ICAM and which cell has which molecule?

A

LFA-1 on T cell

ICAM on APC

these are adhesion molecules which further stabilise cell-cell binding between T cell and APC

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31
Q

what occurs during the interaction between co-stimulatory molecules CD28 and CD80?

A

CD28 on T cell

CD80 on APC

signal 2

co-stimulatory receptor sends extra activation signal

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32
Q

what occurs during the interaction between the APC secreted IL-12 and the T cell?

A

IL-12 not only makes the T cell more likely to become Th1 but also provides the inflammatory signals which reinforce other interactions and signals occurring making them more likely to result in activation

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33
Q

outline the intracellular signalling that leads to T cell activation?

A

phosphorylation of ITAMs

co-receptor signal

activation of ZAP-70

involvement of scaffold proteins and adaptor molecules

activation of PLC-gamma

activation of transcription factors

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34
Q

how does phosphorylation of ITAMs occur during intracellular signalling of a T cell?

A

when TCR binds with MHC-peptide it undergoes conformational change which exposes ITAMs of CD3 molecules

two tyrosine kinases called LCK (attached to bottom of CD4/CD8) and FYN (just chills in the cytoplasm around CD3) phosphorylate the ITAMs as soon as their phosphorylation sites are exposed following conformational change

FYN is the first tyrosine kinase to phosphorylate the ITAMs

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35
Q

where are LCK and FYN located?

A

LCK is constitutively associated with cytoplasmic domains of CD4 and CD8

FYN associates weakly with cytoplasmic chains of zeta and CD3 chains

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36
Q

how does the co-receptor signal contribute to intracellular signalling of a T cell?

A

CD4/CD8 binds to MHCII/MHCI to stabilise interaction

because LCK bound to bottom of co-receptor, it moves LCK over to where TCR is allowing it to phosphorylate the ITAMs

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37
Q

how does activation of ZAP-70 occur during intracellular signalling of T cell activation?

A

once ITAMs phosphorylated they provide a binding site for ZAP70

this allows ZAP70 to get phosphorylated by LCK

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38
Q

what is the role of scaffold proteins in T cell intracellular signalling?

A

once ZAP70 gets phosphorylated and activated it recruits and phosphorylates the scaffold proteins LAT and SLP76

this leads to recruitment of phospholipase C-gamma (PLC-gamma) to the membrane

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39
Q

how is PLC-gamma activated?

A

once PLC-gamma is recruited to the membrane by LAT and SLP76 then it is phosphorylated by the CD28 signalling cascade

PLC-gamma activation causes it to move to the nucleus to activate three pathways that activate different transcription factors such as NFKB

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40
Q

what is the outcome of T cell intracellular signalling?

A

activation of transcription factors which regulate gene expression including:

  • IL-2 production (T cell proliferation and survival)
  • perforin/granzyme production (T cell cytotoxic function)
  • cytokines (activate other cells depending on type of infection)

remember that the actual T cell isn’t activated yet as that requires the co-stimulation signal from CD28 which comes soon via another pathway

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41
Q

what do T cells need to do once activated and what is this driven by?

A

survive, proliferate quickly, up-regulate metabolism and acquire functions such as cytokine production and killing molecules

all of this is driven by IL-2

this means that the first thing a T cell must do is is get IL-2 made and also get IL-2 receptor made

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42
Q

what happens if there is no CD28 signal?

A

T cell won’t get activated

it needs co-stimulation from CD28-CD80 as this is signal 2

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43
Q

one of the jobs of TCR signalling is recruiting PLC-gamma to signalling complex, what causes PLC-gamma activation?

A

CD28 co-stimulation

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44
Q

what does PLC-gamma do following activation?

A

splits PIP2 into two secondary messengers called DAG and IP3

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45
Q

outline the CD28 signalling cascade?

A

LCK phosphorylates CD28

PI3-kinase binds to phosphorylated CD28 and gets activated

Activated PI3-kinase leads to recruitment of Itk

Itk activates PLC-gamma

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46
Q

what is the role of IP3?

A

IP3 increases intracellular Ca2+ conc. which leads to activation of calcineurin which then activates a transcription factor called NFAT

NFAT controls genes encoding a bunch of cytokines and T cell effector functions including IL-2

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47
Q

what is the first role of DAG?

A

DAG recruits protein kinase C-0 (PKC-0)

PKC-0 activates CARMA

CARMA leads to activation of transcription factor called NFKB

NFKB controls a lot of stuff, mainly IL-2

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48
Q

what is the second role of DAG?

A

DAG recruits RasGRP

RasGRP activates Ras

Ras activates MAP kinase cascade

MAPK activates Fos which is a component of the transcription factor AP-I

AP-I controls mostly IL-2 and some other cytokines

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49
Q

what is the main cytokine produced by the three possible pathways resulting from PLC-gamma activation?

A

IL-2

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50
Q

what T cell functions does IL-2 control?

A

survival

proliferation

metabolism

cytotoxicity

cytokine production

T cell death following immune response

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51
Q

what is the main downstream effect of TCR binding and CD28 co-stimulation?

A

production of IL-2 and IL-2 receptor

this leads to a positive feedback loop for T cell proliferation, survival and growth)

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52
Q

what is the IL-2 receptor?

A

is needed for IL-2 to work which is why activated T cells make both IL-2 and IL-2R

IL-2 receptor has three components; alpha chain, beta chain and gamma chain. The receptor works best with all three

IL-2 is shaped to allow interaction with two receptor chains

IL-2R can functionally signal through intermediate or high affinity receptors only

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53
Q

what is IL-2Ralpha?

A

the alpha chain of IL-2R (also called CD25)

is upregulated upon T cell activation and doesn’t do anything on its own (not responsible for signal transduction)

54
Q

what is IL-2Rbeta?

A

the beta chain of IL-2R (also called CD122)

always present on the T cell but not sufficient enough to drive T cell functions alone

responsible for signal transduction

55
Q

what is IL-2Rgamma?

A

the gamma chain of IL-2R (also called gammaC)

responsible for signal transduction

56
Q

what is an intermediate affinity IL-2 receptor composed of?

A

IL-2Rbeta and IL-2Rgamma

can allow IL-2 signalling but not really enough to drive CD4 T cell functions

57
Q

what is a high affinity IL-2 receptor composed of?

A

IL-2Ralpha, IL-2Rbeta and IL-2Rgamma

58
Q

what does it mean if the IL-2 receptor is transiently expressed?

A

means the receptor isn’t expressed all the time e.g. in effector T cells

this probably means you don’t want that cell proliferating or carrying out its functions all the time

59
Q

what does it mean if the IL-2 receptor is constitutively expressed?

A

means the receptor is expressed all the time

probably means you want that cell carrying out its function all the time

60
Q

what does the kind of IL-2 receptor expressed on cell tell you?

A

tells you the kind off effect IL-2 production will have

for example IL-2 signals through:

  • constitutively expressed IL-2Rabgamma in Tregs
  • constitutively expressed IL-2Rbgamma in NK cells
  • transiently expressed IL-2Rabgamma in effector T cells
61
Q

why can Tregs outcompete effector T cells?

A

cause they constitutively express high affinity IL-2 receptor well effector T cells only transiently express high affinity IL-2R

reminder that high affinity IL-2 receptor has alpha, beta and gamma chain

62
Q

outline the interaction between IL-2 and IL-2R?

A

IL-2 interacts with IL-2Ra

IL-2 undergoes conformational change that allows it to interact with IL-2Rb

gamma chain is recruited

IL-2 binding leads to dimerisation of IL-2Rb and gammaC

this dimerisation is required for signalling to occur

63
Q

many cells respond to IL-2, but what does the variation in sensitivity depend on?

A

types of IL-2R expressed (high affinity, intermediate affinity)

induced (transient) vs constitutive expression of IL-2R

64
Q

what are the three IL-2 signalling pathways?

A

JAK-STAT pathway

RAS-MAP kinase pathway

PI3K pathway

65
Q

outline IL-2R signalling via JAKSTAT?

A

IL-2R has no intrinsic protein kinase domains and so relies on janus family kinases (JAKs) to initiate signalling

JAK activation leads to phosphorylation of beta chain of IL-2R

SH2 domains on STAT proteins bind phosphorylated receptors

transcription factors called STATS get phosphorylated, dimerise and translocate to nucleus

the main outcome of this is expression of IL-2R alpha chain (CD25) so more receptor available for more interaction and thus more activation

also activates FasL (cytotoxicity) and FOXP3 (Tregs)

66
Q

what are the main outcomes of the IL-2 signalling pathways PI3K signalling and Ras-MAPK signalling?

A

main outcome is production of more IL-2

also production of cell cycle proteins (proliferation) and CTLA4 (negative feedback)

67
Q

what does IL-2 control?

A

T cell:

activation
proliferation
survival
polarisation
death

68
Q

what gene expression is induced by IL-2?

A

more IL-2
more IL-2 signalling
proliferation and cell cycle
glucose uptake (energy)
more cytokines and cytokine receptors
death pathways

all this leads to more T cell activation

69
Q

outline the IL-2 - IL-2R autocrine loop?

A

TCR activation via TCR and costimulation results in activation of NFAT, NFKB and AP1 which leads to expression of IL-2 and IL-2R alpha chain

IL-2 binds to the IL-2R alpha chain intimating IL-2 signalling which activates STATs leading to expression of IL-2 and IL-2R

70
Q

how do you stop the autocrine loop of IL-2 - IL-2R and decrease T cell activation?

A

IL-2 negative feedback

signals from dendritic cells via TCRs are different after antigen clearance meaning that the signalling pathways within the T cell are different

downstream effect is signals saying do less to the T cell

71
Q

what are the two ways in which a T cell can undergo negative feedback to reduce IL-2 and IL-2R production?

A

SOCS

PTEN/BLIMP

72
Q

outline the SOCS method of IL-2 regulation?

A

SOCS = suppressor of cytokine signalling

  1. activation signal
  2. end of infection signal = SOCS transcribed
  3. SOCS inhibit IL-2 signalling

SOCS are induced by STAT activation from IL-2 signalling and inhibit JAKS binding stopping IL-2 signalling following the end of infection signal

many cytokines self-regulate by expressing SOCS proteins

the main point is they inhibit cytokine signalling after the cytokine has had its effect

73
Q

outline the PTEN and BLIMP-1 methods of IL-2 regulation/negative feedback?

A

IL-2 induces PRDM1 gene that encodes a transcription factor called BLIMP-1

BLIMP-1 then represses IL-2 transcription thus stopping the feedback loop

in contracting T cell you’ll see lots of BLIMP and not so much IL-2 production

74
Q

what are T cell subsets classified based on?

A

cytokines that induce differentiation

transcription factors that control gene expression

cytokines produced by the cells

75
Q

outline the process of JAK-STAT signalling?

A
  1. binding of cytokine to receptor causes receptor to dimerise
  2. this brings receptor associated JAKs in close
  3. JAKs phosphorylate each other on tyrosine residues (cause no phosphorylation sites on cytokine receptor so has to be done via JAKS)
  4. activated JAKs phosphorylate receptor
  5. receptor phosphorylation creates binding sites for STATs
  6. STATs bind, get phosphorylated by JAKs, then dissociate
  7. STATs dimerise and translocate to nucleus to make shit happen
76
Q

outline the molecular process from activation to effect of Th1 cells?

A

pathogen activates APC indicating IFN-gamma response will be best to get rid of it

APC takes pathogen antigen to specific TCR activating it and giving costimulatory signal leading to proliferation and IL-2 and IL-2R expression. At the same time APC making IL-12 which binds IL-12R

IL-12R signals via JAK protein causing dimerisation of two STAT4 TFs which go off to nucleus inducing mild IFN-gamma expression and Tbet expression

Once Tbet expressed you can get v effective IFN-gamma production from the IL-12R signalling leading to more Tbet and more IL-12R (positive feedback)

IFN-gamma causes increased TLR and MHC expression, increased chemokine secretion, increased macrophage activation, increased phagocytosis

77
Q

outline the molecular process from activation to effect of Th2 cells?

A

parasite activates APC which takes antigen to specific TCR activating it and giving costimulatory signal leading to proliferation, IL-2 and IL-4 expression

IL-4 binds IL-4R activating JAK protein which causes STAT6 to dimerise and go to nucleus inducing mild production of IL4, 5 and 13 and activating GATA3

Now that we have GATA3 the IL-4R signalling leads to strong expression of the cytokines (IL-4, 5 13) starting positive feedback loop where more GATA3 expressed leading to more cytokines

IL-4 stimulates B cells to make IgE, IL-5 activates mast cells and basophils, IL-13 stimulates mucus production; the idea of this is that you can fuck up a parasite and then clear it out with mucus

Th2 response also associated with atopy and allergy

78
Q

outline the molecular process from activation to effect of Th17 cells?

A

Th17 cells have two receptors that need to be activated: IL6R and TGFbetaR (we ignore this one cause signalling weird)

IL6R signals through JAKSTAT causing dimerisation of STAT3 leading to production of IL-17 and expression of RORgammaT. Also expression of IL21 and IL21R

so now getting positive feedback but also second signal through IL21>IL21R>STAT3>RORgammaT. This leads to production of IL-17, 21, 23 and 23R

So IL21R reinforcement leads to IL23R reinforcement and ultimately makes Th17 super stable phenotype

IL-17 recruits neutrophils, promotes inflammation
IL-22 stimulates epithelial cells to make antimicrobial peptides
IL-23 promotes maintenance of Th17 phenotype

Th17 in general associated with chronic inflammatory diseases e.g. MS, IBD

79
Q

what do Tregs do?

A

immune responses cause damage to us too so need to control scope and size of immune response

also need to control autoreactive cells which escape regulation in development and need to control autoimmune responses

Tregs do all this

80
Q

what is the difference between thymic and induced Tregs?

A

thymic Tregs come from thymus and already are a Treg

induced Tregs develop from naive T cells in periphery in response to antigen activation and cytokine signals (these ones are a type of T cell subset?)

81
Q

how do you define a Treg?

A

constitutively expresses IL-2Ra (CD25) chain all the time (makes sense cause they need be ready to respond to IL-2)

in conjunction with low IL-7Ra chain (CD127) expression (used to define human Tregs)

this is the case for both tTregs and iTregs

can also look at FOXP3 TF which is master regulator for Treg function; represses transcription of pro-inflammatory genes (e.g. IL-2, IFN-gamma), enhances transcription of anti-inflammatory genes (e.g. IL-10, CTLA-4)

demethylation of the FOXP3 locus only occurs in Tregs with stable expression of FOXP3 (not conventional T cell that upregulate FOXP3 transiently after activation)

82
Q

why is it kinda hard to identify Tregs using CD25 and FOXP3?

A

FOXP3 an intranuclear protein so not always possible to identify

CD25 and FOXP3 alone cannot be used to identify Tregs as conventional T cell population can upregulate both markers after activation

83
Q

outline the molecular process from activation to effect of induced Tregs?

A

DC presents something like commensal antigen or damaged self antigen which suggests might be time to tone down immune response to specific TCR

signalling via TGFbetaR>JAK>STAT3 and also activation of STAT5 from IL2R leading to production of FOXP3, IL-10 and TGFbeta

the Treg then can suppress effector T cell function, activation and proliferation and also promote healing

84
Q

why might you get a lot of weird hybrids of both Th17 and Tregs?

A

they both need TGFbetaR

85
Q

outline what cytokine mediated suppression by IL-10 does?

A

Tregs make IL-10 which shuts down a bunch of immune response functions e.g.

inhibits: antigen presentation by macrophages, pro-inflammatory cytokine production by macrophages, costimulation signals by macrophages

enhances production of anti-inflammatory IL-1 receptor antagonist

down-regulates IFN-gamma and IL-2 production

induces anergy

stimulates secretory IgA production by B cells

86
Q

outline cytokine mediated suppression by TGFbeta?

A

As well as IL-10, Tregs make TGFbeta which:

converts naive T cells to Tregs

inhibits activation of T cells and activation of macrophages

heals intestinal epithelial barrier

87
Q

outline Treg immune suppression by cell surface molecules CTLA4?

A

Tregs can upregulate CTLA4 which preferentially binds same ligand (CD80/CD86) as CD28 (signal 2) thus inhibiting TCR signalling

So if lots of Tregs in system where APCs activating T cells they will get in the way cause they upregulate CTLA4 which binds CD80 with more affinity than CD28 so slow immune response

shortens dwell time between naive T cells and APCs and has similar effect to ICOS

88
Q

outline Treg immune suppression by metabolic control?

A

T cells need a shit load of glucose/energy for activation which is supported through IL-2 signalling so Tregs can constitutively express IL-2Ra (CD25) which outcompetes other T cells for IL-2

Tregs can also induce T cell anergy (I think this might be through the above method tho??)

Tregs can produce tryptophan metabolites which inhibit T cell growth

89
Q

why do T cells display plasticity and heterogeneity and how is this important?

A

throughout immune response T cells needed for different jobs e.g. inflammation to healing. Many disease require multiple layers of immune response, these differences usually influenced by cytokines (which also change over immune response)

this is clinically important as T cell phenotypes determine disease progression/patient outcome and immune therapies try to target this. Diseases like IBS show a lot of T cell heterogeneity/plasticity

90
Q

what is T cell plasticity?

A

the ability of a T cell to take on characteristics of many subsets simultaneously or at different times

basically T cells change

91
Q

what is differentiation/polarisation of T cells?

A

reversible maturation based off early cytokine signals that allows cells to undergo alternate fates depending on environment

this differentiation is then reinforced by master transcription factors

remember that differentiation can then be reprogrammed based off of other signals (plasticity)

92
Q

what do we see lots of in transition phases of T cells?

A

co-expression

93
Q

what are the four ways that T cell subsets are regulated?

A

cytokine mediated inhibition

transcriptional inhibition of T cell subsets

epigenetic control of T cell subsets

TCR signalling

94
Q

what are the four ways that T cell subsets are regulated?

A

cytokine mediated inhibition

transcriptional inhibition of T cell subsets

epigenetic control of T cell subsets

TCR signalling

95
Q

what are the ways cytokines control T cell subsets?

A

cytokine combinations can drive hybrid T cells

cytokines can inhibit activation of other T cell subsets (e.g. Th1 making IFN-gamma can inhibit Th2 and Th17 development) (direct inhibition)

cytokine inhibition of T cell subsets via APC’s (e.g. Th1 cytokine prime DC to not be able to make Th2) (indirect inhibition)

96
Q

what is transcriptional control of T cell subsets?

A

during T cell differentiation toward one lineage the other lineages are suppressed as their is mutual exclusivity among master transcription factors (the one that gets primed first wins) and further cross regulation occurs through repression of TFs

97
Q

what are the master regulators of the main T cell subsets?

A

Th1 - Tbet

Th2 - GATA3

Th17 - RORgammaT

Treg - FOXP3

98
Q

what are the six main types of transcriptional regulation?

A

pioneer

antagonism

synergy

competition

redistribution

99
Q

what is pioneer transcriptional regulation?

A

initial polarising signal (STATs coordinate cytokine signal to get transcription of more cytokines)

100
Q

what is antagonism transcriptional regulation?

A

transcription factors competing for binding sites

this could be due to two cytokine activating two STATs making them compete for the binding site

101
Q

what is synergy transcriptional regulation?

A

transcription factors finding friends to help them bind

this occurs in the form of TF needing a co-factor to help it bind

102
Q

what is competition transcriptional regulation?

A

transcription factors fighting over their friends

this occurs when common molecules required for binding e.g. FOXP3 and RORgammat both need the same co-factor so might have to scrap for it

103
Q

what is redistribution transcriptional regulation?

A

transcription factors moving to new places

occurs when two different transcription factors expressed and can bind in different places

104
Q

what is modulation transcriptional regulation?

A

transcription factors change activity of other molecules

occurs when one transcription factor can change the binding of another transcription factor

105
Q

what is epigenetic control of T cell subsets?

A

epigenetic control activation and repression of genes

differentiated T cells divide and daughter cells keep the same differentiation programme by (a) self reinforcing transcription factor networks and (b) epigenetic mechanisms (stable and heritable programme BUT with ability to change)

mechanisms of epigenetic control works by two major substrates:

  • methylation of DNA (usually repressive = gene silencing)
  • chromatin/histone remodelling (activation or repression)
106
Q

how do we know epigenetics is involved in controlling T cell subsets?

A

inhibit histone modification in naive T cells and it makes IFN-gamma and IL-4

inhibit DNA methylation in naive T cells and it makes IFN-gamma

this indicates somewhere in these cells things are being told not to be made but if you take away inhibitory signal they make it

107
Q

give an example of epigenetic control of T cells via histone modification?

A

if you activate a cell under Th2 conditions you get a stop signal for IFNgamma but if under Th1 you get a go signal and start making it

i.e. there are lots of repressive histone modifications keeping lots of genes silent without changing DNA sequence

108
Q

give an example of epigenetic control of T cells via methylation?

A

if you add IL-12 to naive T cell and it becomes Th1 you get demethylation of Tbet and IFN-gamma

109
Q

at what levels do T cell changes occur?

A

cytokine level, binding level and epigenetic level

110
Q

outline how TCR signalling strength is involved in controlling T cell subsets?

A

TCR affinity generates different signalling strength pathways in cell

this can lead to activation of different transcription factors and therefore different cytokine genes e.g.

  • tuning receptiveness of cell to different cytokines
  • inducing expression of specific cytokine receptors
  • impinging directly on activation of specific STATs
111
Q

T cells with different functions use different metabolic pathways to do what?

A
  • generate energy stores to promote survival
  • produce everything they need for growth and proliferation

cytokines can promote different metabolic pathways in T cells and these metabolic pathways are closely linked by shared fuel inputs

112
Q

what are some of the major metabolic pathways in T cells?

A

glycolytic metabolic pathway

fatty acid oxidation

fatty acid synthesis

113
Q

outline glycolysis in T cells?

A

relatively inefficient but supports anabolic growth (so uses lots of energy very quick)

pro-growth signal pathways (e.g. PI3K and MAPK) promote use of glycolytic metabolism

most important metabolic pathway for rapidly proliferating cells

114
Q

outline the TCA cycle/OX-PHOS in T cells?

A

highly efficient meaning cells can stay alive without using many resources

used in most quiescent/non-proliferating cells

supports oxidative phosphorylation (OX-PHOS)

115
Q

outline fatty acid oxidation (FAO) and fatty acid synthesis (FAS) in T cells?

A

FAO = conversion of fatty acids into products the cell uses to generate energy (i.e. using stuff to get energy which is then used for stuff like FAS)

FAS = lets cells make lipids as building blocks for cell growth and proliferation (i.e. what u need to build the stuff you need to make more T cells)

116
Q

what does metabolism determine in T cells?

A

ability to transition from naive to effector to memory phenotype

this is because specific T cell subsets require distinct metabolic pathways to match their functional requirements and to allow survival

117
Q

outline the molecular metabolic process behind activation of T cells?

A

during activation T cells switch to aerobic glycolysis (and glutamine catabolism)

this switch is mediated by signalling pathways downstream from TCR, co-stimulation and cytokines

these pathways include MAPK/ERK, PI3K, mTOR, NFKB

this leads to activation of TFs like HIF-1alpha which induce genes important for glycolysis (the main metabolic pathway for activated T cells)

all of this is mediated by mTOR

118
Q

outline the metabolic switch during naive to effector T cell transition?

A

naive T cell (quiescent) - OXPHOS, low lactate, low nutrient uptake

activated T cell - up regulates glycolysis, OXPHOS, mTOR, HIF-1alpha and cell gets bigger in general

119
Q

outline the metabolic switch during transition from effector to memory T cell?

A

glycolysis main pathway in activated cell

when you transition to memory you just dial this back and bring out fatty acids a bit more

so memory cells are small and quiescent like naive cells but they have to retain their phenotype so that can respond quickly

like lying down but with their running clothes on

120
Q

what are the metabolic pathways in T cell activation controlled by?

A

TCR signalling cascade

presence of cytokines

availability of nutrients

121
Q

what is the glucose receptor when do T cells upregulate this during activation?

A

GLUT-1

upregulate very early on in activation cause lots of energy required for activation

122
Q

what is GLUT-1?

A

glucose transporter/receptor

expression upregulated upon T cell activation

expression dependent on activation of PI3K

123
Q

what does PI3K do?

A

activates mTOR

124
Q

what does mTOR signalling do?

A

augments glycolytic metabolism to support growth and proliferation

it is the main controller of the switch to the glycolytic pathway

125
Q

what are the key energy sources for T cells?

A

glucose (particularly important in early activation)

glutamine (T cells increase expression of glutamine transports and deletion of these impairs transition to effector)

lipids or fatty acids (component of cell membranes and provide a high yielding energy source, also supply substrates for cell signalling; demand rapidly increases following activation for membrane synthesis)

126
Q

what are the main metabolic pathways in use in the main effector T cell subsets, memory and Tregs?

A

Th1, 2, 17 - aerobic glycolysis

memory, Treg - fatty acid oxidation (FAO)

127
Q

what happens if you make a knockout with no GLUT-1?

A

T cells can’t grow and proliferate and can’t differentiate in Th1, 2 or 17

they can however still differentiate into Tregs (therefore Treg differentiation doesn’t require the glucose pathway)

128
Q

what is mTOR?

A

mediates the switch to glycolysis

two different mTOR complexes which do different things and are regulated by different stimuli

mTORC1 controls cell growth and division and responds to nutrient availability

mTORC2 responds to growth factors and cytokines and controls response to those cytokines (i.e. differentiation pathways)

one or both of these will be activated depending on signals coming in and the ratio of expression dictates what subset the T cell becomes

129
Q

outline the specific mTOR activations the main T cell subsets, what does this show?

A

Th1 - mTORC1 upregulated

Th2 - mTORC1, mTORC2 upregulated

Th17 - mTORC1, HIF1alpha upregulated

Treg - AMPK upregulated

shows that different T cell subsets do different jobs and so the way they get and use energy is different from one another

130
Q

why is it that Tregs don’t need much mTORC1?

A

cause mostly use OXPHOS and fatty acid oxidation (FAO) to produce energy

different metabolic requirement to the effector T cells which use glycolysis and fatty acid synthesis (FAS)

MICR334 - Advanced Immunology (4 decks)

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