adaptive immunity - T cells Flashcards
(125 cards)
1
Q
what T cells activate B cells in the lymph node?
A
T follicular helper cells
2
Q
what T cells activate macrophages?
A
Th1 cells (CD4+)
3
Q
through what vessels to T cells leave lymph node towards site of infection?
A
efferent lymphatic vessels -> thoracic duct -> blood stream
4
Q
which Th1 cytokines promote what at the site of infection?
A
- granzyme and porforin trigger cytotoxic T cell killing
- IFN-y trigger macrophage ROS killing
5
Q
what ligand on CTL binds to what on infected cells? this triggers what?
A
FasL on CTL binds to Fas on infected cell, triggering lysis/apoptosis
6
Q
what directs T cell differentiation into effector cell types?
A
cytokines from APCs
7
Q
what cytokines promotes T cell proliferation?
A
IL-2
8
Q
what 3 categories can t cells differentiate into?
A
CD4+ T helper cells
CD8+ T cells
Regulatory T cells
9
Q
what is cool about an activated effector T cell?
A
it does not require co-stimulation to act
10
Q
big picture about effector t cells role?
A
they have the ability to impact the functionality of other immune cells
11
Q
give examples of how different PAMPs trigger different cytokines production and TH differentiation
A
- Viruses stimulate IL-12 to induce TH1 subset
- Worms stimulate IL-4 to induce TH2 subset
12
Q
what signal regulates T helper cell differentiation?
A
signal 3 cytokines (polarizing cytokines) released from APCs
13
Q
describe TH1
A
- polarizing cytokines (signal 3): IFN-Y, IL-12
- produce IFN-y, CD40L
- target bacteria
- STAT1 and 4 -> T-bet
14
Q
describe TH2
A
- polarizing cytokine: IL-4
- produce IL-4, IL-5, IL-13, CD40L
- against Helminth
- STAT6 -> GATA-3
15
Q
describe TH17
A
- polarizing cytokines: TGF-B, IL-6, IL-23
- produce IL-17, IL-22, CD40L
- STAT3 -> RORyT
16
Q
describe TFH
A
- polarizing cytokine: IL-6
- produce IL-21
- STAT3 -> Bcl-6
17
Q
describe Treg
A
- polarizing cytokines: TGF-B, IL-2
- produce TGF-B, IL-10
- inhibit DCs
- STAT5 -> FoxP3
18
Q
what are stat proteins?
A
act as TFs to help differentiate T cells by transcribing genes that also act as TFs
19
Q
what are called the “2nd” TFs involved in T cell differentiations?
A
master transcriptional regulators
20
Q
type 1 vs type 2 response (relating to T cell differentiation)
A
type 1 = intracellular pathogens induce cell-mediated immunity
type 2 = pathogens inducing humoral immunity ex Helminth
21
Q
how is the Th cell differentiation system made flexible?
A
each naive CD4 T cell expresses all of the STAT proteins (stay unphosphorylated until polarizing cytokine activates it)
22
Q
when are Fas ligand and CD40 ligand expressed?
A
on effector T cells surface following signals 1, 2, 3
23
Q
describe Fas and CD40 ligands
A
transmenbrane ligands, part of TNF family, cell-to-cell interaction
24
Q
on what cells are Fas ligand expressed? what do they bind?
A
expressed on effector CD8+ cells for cytotoxic effect and on TH1 cells;
Fas ligand binds Fas on infected cells at the site of infection
25
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
26
name one function of CD40 ligand
bind CD40 and allows for DC licensing and expression of more co-stimulatory molecules
27
what cytokine is required for CD8+ T cells differentiation?
only require IL-2!
28
what does CD8+ T cells required in higher quantity than CD4+ T cells?
CD8+ cells require more co-stimulation (signal 2)
29
where can CD8+ T cells get IL-2 signal from?
autocrine (like usual), but also from Th1 or Th17 cell!
30
what help do CD8+ T cells require for activation?
help of effector CD4+ T cells
31
how do CTLs (effector CD8+ T cells) act?
CTLs recognize and kill infected/tumor cells via recognition with their TCR
32
how do CD8+ T cells usually get activated?
via cross presentation (CD4 effector T cells licenses an APC)
33
how do CD8+ T cells sometimes get activated? (rare)
via activated dendritic cells that have high costimulatory activity
34
what are the 2 methods of cross presentation?
1. sequential: APC gets licensed by CD4+ cell and then interacts with CD8+ cell independently
2. simultaneous: APC interacts with both CD4+ and CD8+ T cells at the same time
35
in cross presentation, what does CD40 signaling lead to?
leads to DC licensing and expression of more costimulatory molecules
36
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
37
remember: What needs to happen to CD4+ T cells in order for CD8+ T cells activation to occur?
1. find its p:MHC Class II match
2. receive all 3 ligands (signals)
3. CD40 ligand gets expressed and binds to CD40 on APC
38
remember: What needs to happen to DCs to allow them to present antigen to both CD4+ and CD8+ T cells?
1. encouter a PAMP
2. travel to lymph node
3. present MHC Class II to CD4+ T cell
4. Gets licensed through CD40 binding
5. Present exogenous antigen on MHC class I to CD8+ T cell
39
what is 4-1BBL?
molecule that provides CD8+ T cell additional costimulatory signal with B7
40
CTLs can kill infected cells in the periphery via what interaction?
TCR and CD8 co-receptor with pMHC Class I
41
in what 2 ways can CTLs kill infected cells?
- Fas-FasL interaction
- granules
42
how does CTL find its match?
binds to nonspecific adhesion molecules on cells until it finds its pMHC match on an infected cell
43
how does killing via Fas-FasL work?
FasL on CTL binds Fas on infected cells -> triggers cleavage of procaspases into caspases -> apoptosis
44
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
45
what contains the CTL granules?
perforin (forms pores) and granzymes B (serine proteases; activate apoptosis)
46
how do granzymes B cause apoptosis?
enters the cytoplasm and cleaves pro-caspase into caspase (like Fas-FasL) causing DNA fragmentation
47
what do cells infected with granzymes display after 40 minutes?
membrane blebbing
48
what do both (Fas and granules) CTL killing method converge onto?
caspase 3 activation
49
what kind of cytokines are FasL and CD40L?
TNF: they are transmembrane ligands (only do cell-to-cell mechanism)
50
remember: how do NK cells recognize infected cells?
lack of MHC class I
51
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
52
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
53
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
54
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
55
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
56
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)
57
since TGF-B is involved in both Th17 and Treg, what decides which one will be differentiated?
IL-6: induces Th17 differentiation after infection
58
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
59
what is something that changes between different effector T cells, and between their resting vs activated form?
cell surface molecules change
60
what do Th1 activate?
macrophage activation, activation and differentiation of naive CTLs
61
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
62
what macrophage's function is induced by Th1?
M1 macrophages (classically-activated macrophages)
63
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
64
what else other than Th1 can activate M1 macrophages?
IFN-Y but secreted from effector CTLs
65
name the other 5 Th1 effector functions (apart from produce IFN-Y and CD40L to activate M1 macrophages)
1. killing infected macrophages
2. helpt CD8+ T cells
3. stimulate increased differentiation of monocytes in bone marrow
4. change the expression of adhesion molecules on neighboring endothelium to recruit more macrophages
5. recruitment of macrophages by chemotaxis
66
in what cases do TH1 cells kill macrophages? how do they do it?
in case of chronically infected macrophages; via Fas on infected cell
67
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
68
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)
69
how do TH1 cells help recruit macrophages by chemotaxis?
secrete chemokine CCL2 that attract macrophages to site of infection
70
describe a granuloma
Core of infected macrophages surrounded by layer of activated macrophages and then layer of TH1 cells
71
what are Th2's effector cytokines? master transcriptional regulator?
IL-4, IL-5, IL-13.
GATA-3.
72
what cells are recruited and activated by Th2 cells?
eosinophils, mast cells, basophils
73
what are dysregulated Th2 responses involved in?
allergies
74
what is th2's TF that activates GATA-3? (what's its stat protein)
STAT 6
75
what are the consequences of helminths infection?
they colonize gut of animals and humans and cause chronic infection
76
what is Th2's response to helminths?
clear pathogen (if not, leads to chronic infection), reduce worm burden, weep and seep, facilitate TISSUE REPAIR
77
what antibody is involved in helminths immune response?
IgE
78
what is IL-13's role (Th2 effector cytokine)
1. Promote epithelial cell turnover and mucous production (weep in weep and sweep response)
2. stimulate smooth muscle cells to contract and lead to worm expulsion (sweep)
79
what macrophages are recruited by Th2?
M2 macrophages: alternatively activated
80
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
81
what is ADCC definition?
killing of antibody-coated target cells by cells with Fc receptors that recognize the CONSTANT region
82
how do Th2 cells activate eosinophils?
via IL-5
83
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
84
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
85
what do basophils do once activated by Th2?
secrete IL-4 and IL-13, activate goblet cells, allow vasodilation, secrete histamines via ADCC
86
what is Th17 cell's signal 3 (differentiation)?
TGF-B, IL-6 and IL-23
87
what are Th17's effector cytokines? master transcriptional regulator? stat protein?
IL-17, IL-22
STAT3 -> RORyT
88
what are Th17's roles?
1. enhance neutrophil responses and mucosal immunity to help respond to extracellular bacteria and fungi
2. has a pro-inflammatory response
3. involved in autoimmune disorders
89
what are IL-17 and IL-22's role
stimulates other cells to secrete more cytokines, chemokines and antimicrobial peptides
90
name 5 inflammatory diseases in which Th17 is involved
- psoriasis
- inflammatory bowel disease
- asthma
- rheumatoid arthritis
- multiple sclerosis
91
name IL-17 and IL-22's common functions
induce antimicrobial peptides by epithelial cells to help killing or slowing replication of bacteria
92
name IL-22's functions
- increase epithelial turnover to retard bacterial growth
93
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
94
what is G-CSF role?
targets bone marrow precursors to differentiate into neutrophils (endocrine function)
95
what's a monoclonal antibody?
antibody produced by a single clone of a B cells
96
what are the 2 approaches to targeting IL-17 in psoriasis using antibodies?
1. IL-17 receptor antagonist
2. Anti-IL-17 neutralizing antibodies
97
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)
98
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
99
how do Tfh recognize B cells?
they recognize pMHC II in b cells
100
how do Treg help to end immune response?
they release inhibitory cytokines once Ag has been removed
101
how are memory cells selected for survival instead of death induction?
we don't know!
102
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
103
when does Fas start being expressed?
most effector cells start expressing Fas after they've done their job
104
what domains are associated with Fas?
death domains DD and death effector domain DED
105
what is CTLA-4?
inhibitory receptor that downregulates T cell activation
106
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
107
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
108
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
109
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
110
what and where if PD-1?
inhibitory receptor expressed on activated T cells that downregulates T cell activation
111
what is PD-1 a marker for?
Marker of T cell “exhaustion”; occurs in chronic diseases
112
what does PD-1 bind to?
PDL-1 (constitutive in many cells) and PDL-2 on APCs during inflammation
113
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
114
what is iTreg's function?
Suppresses immune responses, specifically maintain immune tolerance to self-antigens (prevent autoimmunity)
115
what are natural Tregs?
thymus-derived Tregs selected for high affinity for self peptides to dampen immune response to self-peptides
116
what do natural AND induced Tregs express?
TCR, CD4, IL2Ra, CTLA-4
also FoxP3 gene
117
where do induced (adaptive) Tregs come from?
arise in the periphery from CD4+ T cells
118
what kind of cytokines are Tregs effector cytokines?
IL-10 and TGFB are immunosuppressive/anti-inflammatory cytokines
119
what is IL-10's specific role?
inhibits MHC expression and B7 expression from APCs, can inhibit production of TH1 and TH17 cytokines
120
what is TGF-B specific role?
inhibits T cell proliferation and inhibit the development and function of TH1 and TH2
121
what does CTLA-4 (Expressed by Treg) do?
sequester B7 from APC surface (reduce activation)
122
what does IL2Ra (Expressed by Treg) do?
depletes the local area of stimulating cytokines (sequesters IL-2)
123
what do nTreg recognize?
self-peptide:MHC
124
what is tolerance?
prevention of an immune response against self-proteins
125
what does it mean if a Treg recognizes its p:MHC on an APC?
that APC is presenting a self-peptide
