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MIMM 214 > 24 - T cells VI: TFH, negative regulation & Tregs > Flashcards

24 - T cells VI: TFH, negative regulation & Tregs Flashcards

1
Q

TFH

Signal 3

A

IL-6

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2
Q

TFH

Transcription factors

A

STAT 3 protein activated

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3
Q

TFH

Master transcriptional regulator

A

Bcl-6

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4
Q

TFH

Effector cytokines

A

IL-21
IL-4 (type 2) or IL-17 (type 3) or IFN-y (type 1)

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5
Q

TFH

Function

A

Activate B cells in lymph node

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6
Q

TFH Functions

A

Secrete IL21 & cytokines typical of: … or…or…or
o Type 1: INFy
o Type 2: IL-4
o Type 3:IL-17

Signal activate B cell = produce specific types of antibodies

TFH cells interact directly with B cells

In response to all types of pathogens

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7
Q

TFH recognize

A

pMHCII on B cells

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8
Q

B cell needs

A

different signals for activation

Nature of signal = inform type of antibody produced

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9
Q

Negative regulation – involve

A

receptors, mechanisms & cell types (Tregs)

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10
Q

Immune response contracts w/in

A

10-14 days

After Ag removed – most lymphocytes no longer required & undergo apoptosis
-We don’t need all the clones anymore

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11
Q

Treg cells – help to

A

quell responses by releasing inhibitory cytokines

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12
Q

Clonal contraction

A

Most newly generated B & T cells = lost at the end of primary immune response
-After Ag cleared -> Most effector cells = no longer required

Cells die by apoptosis

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13
Q

Cell death via apoptosis : 2 pathways

A
  • Intrinsic pathway
  • Extrinsic pathway
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14
Q

Intrinsic pathway

A

Death by neglect

IL2Ra & other cytokine receptors expression = transient(impermanent)

Lack of signaling through receptors-> absence of survival signal –> apoptosis

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15
Q

Extrinsic pathway

A

o Triggered by Fas-FasL
o Involved CTLs
o Leads to apoptosis

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16
Q

Majority of effector T cells die (~90%) – leaving

A

leaving behind antigen-specific memory T cells

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17
Q

Memory cells respond with

A

heightened reactivity to a subsequent exposure to same Ag
o Secondary response = faster & more robust  more effective

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18
Q

Inhibitory/Regulatory Receptors

A

CTLA-4
PD-1

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19
Q

CTLA-4: downregulates…

A

Down-regulates T cell activation/proliferation/survival

-Binds to B7.1/B7.2 with higher affinity than CD28 –> shuts down signaling pathways & prevent excessive uncontrolled immune response
-Keep it balanced

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20
Q

CTLA-4: Induced w/in …

A

24 hours after activation  peaks 2-3 days post stimulation
-CTLA-4 found intracellular –>phosphorylation allows it to be expressed on cell membrane

Must be called on to be expressed on cell surface - only when T cell activated
-Post-translational regulation

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21
Q

1 CTLA-4 molecules can bind

A

2 B7 molecules

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22
Q

CTLA can … B7

A

Binding sequesters (hugs) B7 & prevent binding to CD28

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23
Q

Sometimes = CTLA-4 can

A

strip B7 molecules from antigen-presenting cells & remove them from APC surfaces & endocytose it

24
Q

CD28 = expressed on

A

naïve T cells

25
But surface expression of CTLA-4 = induced
after activation of naïve T cells Making activated T cells less sensitive than naïve T cells to stimulation by APCs &restricting IL-2 production -Prevent overgrowth of lymphocytes With each exposure – make more clones that we don’t need as the antigen is cleared
26
PD-1:
o Can be expressed on activated T cells o Binds PDL-1 (Expressed by many cells) & PDL-2 (on APC during inflammation) o Marker of T cell exhaustion = occur in chronic diseases
27
PD-1 signaling =
downregulate T cell activation/proliferation & function
28
o Blocking PD-1/PDL-1/CTLA-4 =
targets of cancer therapies
29
Regulation: cellular mechanisms
T regs
30
i in iTreg
i=induced (Arise in lymph node)  have gotten all 3 signals
31
T regs Signal 3
IL-2 TGFb
32
T regs Transcription factors
STAT 5
33
T regs Master transcriptional regulation regulator
FoxP3
34
T regs Effector cytokines
IL-10 TGFb (anti-inflammatory cytokines)
35
T regs Function
Suppresses immune responses -maintain immune tolerance to self-antigens (prevent autoimmunity) -prevent attack to safe-self & safe non-self
36
TREG subsets (2)
* Natural TREG = nTREG * Induced (Adaptive) TREG:
37
Natural TREG = nTREG
Thymus-derived -Leave thymus as regulatory T cells Selected for high affinity for self-peptides - but to dampen immune response to them Express TCR, CD4, IL2Ra & CTLA-4 -Unable to provide IL-2 = so they rely on other cells Also prevent other T cell that secret IL-2 from overgrowth Express FoxP3
38
Induced (Adaptive) TREG:
Arise in periphery from CD4+ T cells Express TCR, CD4, IL2R, CTLA-4 Express FoxP3 – some expectations
39
Induced & natural regulatory T cells function
* Secrete IL-10 & TGFb * Represses other immune cells – mainly T cells Prevent inappropriate immune responses -Autoimmune responses
40
TREG function
TREG cells negatively regulate immune responses
41
TREG function, deplete...
o Deplete local area of stimulating cytokines  Express IL2Ra (CD25) chain - sequester IL-2 * They don’t make IL-2
42
TREG function,B7
o B7 sequestration by CTLA-4  Inhibit APC activity by reducing co-stimulatory molecules expression & pro-inflammatory cytokine secretion  Reduce T cell differentiation & activation
43
TREG function, produce....
o Produce immunosuppressive cytokines  IL-10  TGFb
44
TREG function, directly
Directly kill T cells through granzymes & metabolic disruption * Like CTL
45
IL-10
Inhibit production of TH1 & TH17 cytokines
46
TGFb
o Inhibit T cell proliferation o Inhibit development & function of TH1 & TH2
47
T cells = specific to
peptides mainly dangerous non-self
48
TREG = specific to
peptides mainly self/safe non-self o nTREG - recognize slef-peptide:MHC - arise in thymus o iTREG- recognize peptide:MHC (can be self or commensal Ag)  arise in periphery
49
Majority of autoreactive T cells =
deleted in developmental process in thymus -some T cells can escape & cause allergies/autoimmunity
50
Tolerance:
preventing an immune response against self-proteins
51
If TREG recognize its p:MHC on APC = APC presenting self-peptides
TREG secrete cytokines – inhibit neighbouring (& potentially autoreactive) T cells that recognize other self-peptides:MHC being presented by same cell from getting activated Lots of different peptides are presented on different MHC on surface of APC but the peptides all come from same source (Self-protein)
52
Treg Can supress
APCs & other T cells
53
TH1 cells, CTLs cells, TH17 cells or TREG Kills chronically infected macrophages
TH1 cells
54
TH1 cells, CTLs cells, TH17 cells or TREG Can inhibit APC activity
TREG
55
TH1 cells, CTLs cells, TH17 cells or TREG Secrete cytokines that increase epithelial turnover
TH17 cells
56
TH1 cells, CTLs cells, TH17 cells or TREG Fas-FasL mediated killing
CTLs cells

MIMM 214 (39 decks)

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