adaptive immunity - T cells Flashcards
what T cells activate B cells in the lymph node?
T follicular helper cells
what T cells activate macrophages?
Th1 cells (CD4+)
through what vessels to T cells leave lymph node towards site of infection?
efferent lymphatic vessels -> thoracic duct -> blood stream
which Th1 cytokines promote what at the site of infection?
- granzyme and porforin trigger cytotoxic T cell killing
- IFN-y trigger macrophage ROS killing
what ligand on CTL binds to what on infected cells? this triggers what?
FasL on CTL binds to Fas on infected cell, triggering lysis/apoptosis
what directs T cell differentiation into effector cell types?
cytokines from APCs
what cytokines promotes T cell proliferation?
IL-2
what 3 categories can t cells differentiate into?
CD4+ T helper cells
CD8+ T cells
Regulatory T cells
what is cool about an activated effector T cell?
it does not require co-stimulation to act
big picture about effector t cells role?
they have the ability to impact the functionality of other immune cells
give examples of how different PAMPs trigger different cytokines production and TH differentiation
- Viruses stimulate IL-12 to induce TH1 subset
- Worms stimulate IL-4 to induce TH2 subset
what signal regulates T helper cell differentiation?
signal 3 cytokines (polarizing cytokines) released from APCs
describe TH1
- polarizing cytokines (signal 3): IFN-Y, IL-12
- produce IFN-y, CD40L
- target bacteria
- STAT1 and 4 -> T-bet
describe TH2
- polarizing cytokine: IL-4
- produce IL-4, IL-5, IL-13, CD40L
- against Helminth
- STAT6 -> GATA-3
describe TH17
- polarizing cytokines: TGF-B, IL-6, IL-23
- produce IL-17, IL-22, CD40L
- STAT3 -> RORyT
describe TFH
- polarizing cytokine: IL-6
- produce IL-21
- STAT3 -> Bcl-6
describe Treg
- polarizing cytokines: TGF-B, IL-2
- produce TGF-B, IL-10
- inhibit DCs
- STAT5 -> FoxP3
what are stat proteins?
act as TFs to help differentiate T cells by transcribing genes that also act as TFs
what are called the “2nd” TFs involved in T cell differentiations?
master transcriptional regulators
type 1 vs type 2 response (relating to T cell differentiation)
type 1 = intracellular pathogens induce cell-mediated immunity
type 2 = pathogens inducing humoral immunity ex Helminth
how is the Th cell differentiation system made flexible?
each naive CD4 T cell expresses all of the STAT proteins (stay unphosphorylated until polarizing cytokine activates it)
when are Fas ligand and CD40 ligand expressed?
on effector T cells surface following signals 1, 2, 3
describe Fas and CD40 ligands
transmenbrane ligands, part of TNF family, cell-to-cell interaction
on what cells are Fas ligand expressed? what do they bind?
expressed on effector CD8+ cells for cytotoxic effect and on TH1 cells;
Fas ligand binds Fas on infected cells at the site of infection
on what cells are CD40 ligand expressed? what do they bind?
expressed by Th1, Th2, Th17, Tfh cells;
bind CD40 on B cells and innate immune cells to activate them
name one function of CD40 ligand
bind CD40 and allows for DC licensing and expression of more co-stimulatory molecules
what cytokine is required for CD8+ T cells differentiation?
only require IL-2!
what does CD8+ T cells required in higher quantity than CD4+ T cells?
CD8+ cells require more co-stimulation (signal 2)
where can CD8+ T cells get IL-2 signal from?
autocrine (like usual), but also from Th1 or Th17 cell!
what help do CD8+ T cells require for activation?
help of effector CD4+ T cells
how do CTLs (effector CD8+ T cells) act?
CTLs recognize and kill infected/tumor cells via recognition with their TCR
how do CD8+ T cells usually get activated?
via cross presentation (CD4 effector T cells licenses an APC)
how do CD8+ T cells sometimes get activated? (rare)
via activated dendritic cells that have high costimulatory activity
what are the 2 methods of cross presentation?
- sequential: APC gets licensed by CD4+ cell and then interacts with CD8+ cell independently
- simultaneous: APC interacts with both CD4+ and CD8+ T cells at the same time
in cross presentation, what does CD40 signaling lead to?
leads to DC licensing and expression of more costimulatory molecules
difference between sequential and simultaneous cross presentation cell proliferation signal?
in sequential, CD8+ T cell only recieve its own IL-2 signal (autocrine).
in simultaneous, CD8+ recieves IL-2 from both CD4+ and from itself
remember: What needs to happen to CD4+ T cells in order for CD8+ T cells activation to occur?
- find its p:MHC Class II match
- receive all 3 ligands (signals)
- CD40 ligand gets expressed and binds to CD40 on APC
remember: What needs to happen to DCs to allow them to present antigen to both CD4+ and CD8+ T cells?
- encouter a PAMP
- travel to lymph node
- present MHC Class II to CD4+ T cell
- Gets licensed through CD40 binding
- Present exogenous antigen on MHC class I to CD8+ T cell
what is 4-1BBL?
molecule that provides CD8+ T cell additional costimulatory signal with B7
CTLs can kill infected cells in the periphery via what interaction?
TCR and CD8 co-receptor with pMHC Class I
in what 2 ways can CTLs kill infected cells?
- Fas-FasL interaction
- granules
how does CTL find its match?
binds to nonspecific adhesion molecules on cells until it finds its pMHC match on an infected cell
how does killing via Fas-FasL work?
FasL on CTL binds Fas on infected cells -> triggers cleavage of procaspases into caspases -> apoptosis
how does CTL granule-mediated killing work?
TCR:pMHC recognition -> Reorganization of cytoskeleton and cytoplasmic contents to bring granules close to target cell -> granules released
what contains the CTL granules?
perforin (forms pores) and granzymes B (serine proteases; activate apoptosis)
how do granzymes B cause apoptosis?
enters the cytoplasm and cleaves pro-caspase into caspase (like Fas-FasL) causing DNA fragmentation
what do cells infected with granzymes display after 40 minutes?
membrane blebbing
what do both (Fas and granules) CTL killing method converge onto?
caspase 3 activation
what kind of cytokines are FasL and CD40L?
TNF: they are transmembrane ligands (only do cell-to-cell mechanism)
remember: how do NK cells recognize infected cells?
lack of MHC class I
what cytokine do CTLs secrete?
type II IFN: anti-viral cytokine that increases MHC class I on neighboring cells (protect) and activate and recruit macrophages and CD8+ T cells to site of infection
what’s the difference between type 1 IFN and type II?
type I = antiviral effects, secreted by innate cells following PRR activation
type II = also antiviral, secreted by adaptive effector CTLs
name the different effector CD4+ T cells function
- Th1: infections by viruses and intracellular pathogens
- Th2: parasites, extracellular pathogens, allergies, HELMINTHS. target granulocytes
- Th17: infections by extracellular bacteria and fungi, autoimmunity, target neutrophils
- Tfh: activate B cells, stay in lymph nodes
name the cytokines released/expressed by each CD4+ effector T cell
- Th1: IFNY, CD40L
- Th2: IL-4, IL-5, IL-13, CD40L
- Th17: IL-17, IL-22, CD40L
- Treg: IL-10, TGF-B
what is cross-regulation between T cells?
cytokines secreted by effector T cells can suppress other T cells differentiation:
- IL-4, secreted by TH2, inhibits TH1 differentiation
- IFN-g secreted by TH1, inhibits TH2 differentiation
- IL-4 or IFN-g inhibit TH17 differentiation
what protein commits a T cells to its subset? what does it also do?
Master transcriptional regulators.
also involved in crossregulation (ex: T-bet suppresses Th2, GATA3 suppresses Th1)
since TGF-B is involved in both Th17 and Treg, what decides which one will be differentiated?
IL-6: induces Th17 differentiation after infection
what effector CD4+ T cells leave vs stay in the lymph node?
- Th1, Th2, Th17: leave lymph node and migrateb to the site of infection
- Tfh, Treg: stay in the lymph node to activate B cells
what is something that changes between different effector T cells, and between their resting vs activated form?
cell surface molecules change
what do Th1 activate?
macrophage activation, activation and differentiation of naive CTLs
Th1 function basically?
they target macrophages by recognizing pMHC-II, secrete IFN-Y to help killing microbes that persist in macrophages vesicles by inducing TNFa production by macrophages
what macrophage’s function is induced by Th1?
M1 macrophages (classically-activated macrophages)
explain the positive feedback loop of Th1 activation
Th1 secrete IFN-Y -> activate macrophages -> macrophages secrete TNFa -> IFN-Y + TNFa increase MHC I & II expression, CD40, B7, IL-12 -> activates more Th1
what else other than Th1 can activate M1 macrophages?
IFN-Y but secreted from effector CTLs
name the other 5 Th1 effector functions (apart from produce IFN-Y and CD40L to activate M1 macrophages)
- killing infected macrophages
- helpt CD8+ T cells
- stimulate increased differentiation of monocytes in bone marrow
- change the expression of adhesion molecules on neighboring endothelium to recruit more macrophages
- recruitment of macrophages by chemotaxis
in what cases do TH1 cells kill macrophages? how do they do it?
in case of chronically infected macrophages; via Fas on infected cell
how do tH1 cells help CD8+ t cells?
by secreting IL-2 to stimulate CD8+ T cell proliferation in the lymph nodes *can also induce CD4+ t cells proliferation
how do Th1 cells stimulate the differentiation of monocytes in bone marrow
they secrete IL-3 and GM-CSF that circulate in blood and act on precursor in bone marrow (endocrine effect)
how do TH1 cells help recruit macrophages by chemotaxis?
secrete chemokine CCL2 that attract macrophages to site of infection
describe a granuloma
Core of infected macrophages surrounded by layer of activated macrophages and then layer of TH1 cells
what are Th2’s effector cytokines? master transcriptional regulator?
IL-4, IL-5, IL-13.
GATA-3.
what cells are recruited and activated by Th2 cells?
eosinophils, mast cells, basophils
what are dysregulated Th2 responses involved in?
allergies
what is th2’s TF that activates GATA-3? (what’s its stat protein)
STAT 6
what are the consequences of helminths infection?
they colonize gut of animals and humans and cause chronic infection
what is Th2’s response to helminths?
clear pathogen (if not, leads to chronic infection), reduce worm burden, weep and seep, facilitate TISSUE REPAIR
what antibody is involved in helminths immune response?
IgE
what is IL-13’s role (Th2 effector cytokine)
- Promote epithelial cell turnover and mucous production (weep in weep and sweep response)
- stimulate smooth muscle cells to contract and lead to worm expulsion (sweep)
what macrophages are recruited by Th2?
M2 macrophages: alternatively activated
what are M2 macrophage roles?
- aid tissue repair and can form granulomas to trap worms in tissue
- release toxic mediators directly onto the worm by antibody-dependent cell-mediated cytotoxicity ADCC
what is ADCC definition?
killing of antibody-coated target cells by cells with Fc receptors that recognize the CONSTANT region
how do Th2 cells activate eosinophils?
via IL-5
how do eosinophils help get rid of parasites?
they recognize IgE antibodies that bind antigens on the parasite, and degranulate to release MBP that can kill parasites
what do mast cells do once activated by Th2?
they recognize IgE on parasite via ADCC and release granules containing histamine: increase vascular permeability, intestinal motility, inflammatory cells
what do basophils do once activated by Th2?
secrete IL-4 and IL-13, activate goblet cells, allow vasodilation, secrete histamines via ADCC
what is Th17 cell’s signal 3 (differentiation)?
TGF-B, IL-6 and IL-23
what are Th17’s effector cytokines? master transcriptional regulator? stat protein?
IL-17, IL-22
STAT3 -> RORyT
what are Th17’s roles?
- enhance neutrophil responses and mucosal immunity to help respond to extracellular bacteria and fungi
- has a pro-inflammatory response
- involved in autoimmune disorders
what are IL-17 and IL-22’s role
stimulates other cells to secrete more cytokines, chemokines and antimicrobial peptides
name 5 inflammatory diseases in which Th17 is involved
- psoriasis
- inflammatory bowel disease
- asthma
- rheumatoid arthritis
- multiple sclerosis
name IL-17 and IL-22’s common functions
induce antimicrobial peptides by epithelial cells to help killing or slowing replication of bacteria
name IL-22’s functions
- increase epithelial turnover to retard bacterial growth
name IL-17’s functions
- acts on stromal and myeloid cells to trigger G-CSF secretion
- induce chemokine secretion by stromal and epithelial cells to attract neutrophils
- attract more Th17 cells
- induces macrophages to secrete pro-inflammatory cytokines like IL-1B and TNF-a
what is G-CSF role?
targets bone marrow precursors to differentiate into neutrophils (endocrine function)
what’s a monoclonal antibody?
antibody produced by a single clone of a B cells
what are the 2 approaches to targeting IL-17 in psoriasis using antibodies?
- IL-17 receptor antagonist
- Anti-IL-17 neutralizing antibodies
what is Tfh’s signal 3 cytokine for differentiation? stat protein? master transcriptional regulator? effector cytokines?
signal 3: IL-6
STAT 3 -> Bcl-6
secrete IL-21 and either IFNY (type 1), IL-4 (type 2), or IL-17 (type 3)
what is Tfh’s function?
interact directly with and activate B cells to produce specific types of antibodies in response to all types of pathogens
how do Tfh recognize B cells?
they recognize pMHC II in b cells
how do Treg help to end immune response?
they release inhibitory cytokines once Ag has been removed
how are memory cells selected for survival instead of death induction?
we don’t know!
what are the intrinsic and extrinsic pathways for cell death via apoptosis?
- intrinsic: death by neglect; lack of IL2/survival signal
- extrinsic: triggered by Fas-FasL, involves CTLs
when does Fas start being expressed?
most effector cells start expressing Fas after they’ve done their job
what domains are associated with Fas?
death domains DD and death effector domain DED
what is CTLA-4?
inhibitory receptor that downregulates T cell activation
how does CTLA-4 downregulation T cell activation?
it binds to B7.1/B7.2 with higher affinity than CD28 and shuts down signaling pathways
when do we see CTLA-4 appear?
it is induced via post-translational phosphorylation 24h after activation of T cells and peaks 2-3 days post-stimulation
how does CTLA-4 have a higher affinity to B7 than CD28?
One CTLA-4 molecule can bind two B7 molecules and prevent CD28 from binding
what else does CTLA-4 do (apart from stopping T cell activation)?
prevents overgrowth of lymphocytes by making activated T cells less sensitive to stimulation and restricting IL-2 production
what and where if PD-1?
inhibitory receptor expressed on activated T cells that downregulates T cell activation
what is PD-1 a marker for?
Marker of T cell “exhaustion”; occurs in chronic diseases
what does PD-1 bind to?
PDL-1 (constitutive in many cells) and PDL-2 on APCs during inflammation
what are iTreg cells signal 3? effector cytokines? TF? master transcriptional regulator? (induced Treg)
signal 3: IL-2 and TGFB
effector cytokines: IL-10 and TGFB
transcription factors: STAT3
master transcriptional regulator: FoxP3
what is iTreg’s function?
Suppresses immune responses, specifically maintain immune tolerance to self-antigens (prevent autoimmunity)
what are natural Tregs?
thymus-derived Tregs selected for high affinity for self peptides to dampen immune response to self-peptides
what do natural AND induced Tregs express?
TCR, CD4, IL2Ra, CTLA-4
also FoxP3 gene
where do induced (adaptive) Tregs come from?
arise in the periphery from CD4+ T cells
what kind of cytokines are Tregs effector cytokines?
IL-10 and TGFB are immunosuppressive/anti-inflammatory cytokines
what is IL-10’s specific role?
inhibits MHC expression and B7 expression from APCs, can inhibit production of TH1 and TH17 cytokines
what is TGF-B specific role?
inhibits T cell proliferation and inhibit the development and function of TH1 and TH2
what does CTLA-4 (Expressed by Treg) do?
sequester B7 from APC surface (reduce activation)
what does IL2Ra (Expressed by Treg) do?
depletes the local area of stimulating cytokines (sequesters IL-2)
what do nTreg recognize?
self-peptide:MHC
what is tolerance?
prevention of an immune response against self-proteins
what does it mean if a Treg recognizes its p:MHC on an APC?
that APC is presenting a self-peptide
