24 - T cells VI: TFH, negative regulation & Tregs Flashcards
TFH
Signal 3
IL-6
TFH
Transcription factors
STAT 3 protein activated
TFH
Master transcriptional regulator
Bcl-6
TFH
Effector cytokines
IL-21
IL-4 (type 2) or IL-17 (type 3) or IFN-y (type 1)
TFH
Function
Activate B cells in lymph node
TFH Functions
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
TFH recognize
pMHCII on B cells
B cell needs
different signals for activation
Nature of signal = inform type of antibody produced
Negative regulation – involve
receptors, mechanisms & cell types (Tregs)
Immune response contracts w/in
10-14 days
After Ag removed – most lymphocytes no longer required & undergo apoptosis
-We don’t need all the clones anymore
Treg cells – help to
quell responses by releasing inhibitory cytokines
Clonal contraction
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
Cell death via apoptosis : 2 pathways
- Intrinsic pathway
- Extrinsic pathway
Intrinsic pathway
Death by neglect
IL2Ra & other cytokine receptors expression = transient(impermanent)
Lack of signaling through receptors-> absence of survival signal –> apoptosis
Extrinsic pathway
o Triggered by Fas-FasL
o Involved CTLs
o Leads to apoptosis
Majority of effector T cells die (~90%) – leaving
leaving behind antigen-specific memory T cells
Memory cells respond with
heightened reactivity to a subsequent exposure to same Ag
o Secondary response = faster & more robust more effective
Inhibitory/Regulatory Receptors
CTLA-4
PD-1
CTLA-4: downregulates…
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
CTLA-4: Induced w/in …
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
1 CTLA-4 molecules can bind
2 B7 molecules
CTLA can … B7
Binding sequesters (hugs) B7 & prevent binding to CD28
Sometimes = CTLA-4 can
strip B7 molecules from antigen-presenting cells & remove them from APC surfaces & endocytose it
CD28 = expressed on
naïve T cells
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
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
PD-1 signaling =
downregulate T cell activation/proliferation & function
o Blocking PD-1/PDL-1/CTLA-4 =
targets of cancer therapies
Regulation: cellular mechanisms
T regs
i in iTreg
i=induced (Arise in lymph node) have gotten all 3 signals
T regs
Signal 3
IL-2
TGFb
T regs
Transcription factors
STAT 5
T regs
Master transcriptional regulation regulator
FoxP3
T regs
Effector cytokines
IL-10
TGFb (anti-inflammatory cytokines)
T regs
Function
Suppresses immune responses
-maintain immune tolerance to self-antigens (prevent autoimmunity)
-prevent attack to safe-self & safe non-self
TREG subsets (2)
- Natural TREG = nTREG
- Induced (Adaptive) TREG:
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
Induced (Adaptive) TREG:
Arise in periphery from CD4+ T cells
Express TCR, CD4, IL2R, CTLA-4
Express FoxP3 – some expectations
Induced & natural regulatory T cells function
- Secrete IL-10 & TGFb
- Represses other immune cells – mainly T cells
Prevent inappropriate immune responses
-Autoimmune responses
TREG function
TREG cells negatively regulate immune responses
TREG function, deplete…
o Deplete local area of stimulating cytokines
Express IL2Ra (CD25) chain - sequester IL-2
* They don’t make IL-2
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
TREG function, produce….
o Produce immunosuppressive cytokines
IL-10
TGFb
TREG function, directly
Directly kill T cells through granzymes & metabolic disruption
* Like CTL
IL-10
Inhibit production of TH1 & TH17 cytokines
TGFb
o Inhibit T cell proliferation
o Inhibit development & function of TH1 & TH2
T cells = specific to
peptides mainly dangerous non-self
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
Majority of autoreactive T cells =
deleted in developmental process in thymus
-some T cells can escape & cause allergies/autoimmunity
Tolerance:
preventing an immune response against self-proteins
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)
Treg Can supress
APCs & other T cells
TH1 cells, CTLs cells, TH17 cells or TREG
Kills chronically infected macrophages
TH1 cells
TH1 cells, CTLs cells, TH17 cells or TREG
Can inhibit APC activity
TREG
TH1 cells, CTLs cells, TH17 cells or TREG
Secrete cytokines that increase epithelial turnover
TH17 cells
TH1 cells, CTLs cells, TH17 cells or TREG
Fas-FasL mediated killing
CTLs cells
