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T cell Flashcards

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1
Q

signal 3 of t cell

A

direct differentiation

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2
Q

result of signals

A

activation
proliferation
differentiation
survival

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3
Q

Activation=

A

prolifertion + differentiation

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4
Q

proliferation and differentiation

activated T cell

A

proliferate in response to IL-2
differentiate to:
CD4+ (TH1, 2, 17, reg, fh) and CD8+ (cytotoxic t lymphocyte)

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5
Q

naïve T cells -> effector t cells

A

receive 3 signals
intracellular signal
activate different transcription factor
express different molecules

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6
Q

cd8+ t cells

A

ctl (cytotoxic t lymphocyte)
kill infected cells (bind with MHC 1, don’t need co-stimulation (signal2))

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7
Q

signal 3 cytokines

A

polarizing cytokines

PRR on APC bind with different PAMPs, create different cytokines

differentiate of different t cells

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8
Q

signal 3 effect (pathway)

A

cytokine (from APC)
STAT protein (TF)
Master transcriptional regulator (also TF)
determine cell type
produce different cytokine

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9
Q

fact

each naïve cd4+ t cell express all the STAT protein

A
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10
Q

Fas ligand and CD40 ligand

Lecture 2

A

express on effector T cells not on naïve T cells
crucial for effector T cell function
transmembrane ligands, part of TNF family

Included in genes that are induced following signals 1,2,3

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11
Q

express, bind, funciton

Fas ligand

A

express on the surface of effector CD8+ T cells and Th1 cells
-CD8+ used for cytotoxic effect

bind Fas on the surface of the infected cells in the periphery (site of infection)

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12
Q

express, bind, funciton

CD40 ligand

A

expressed by Th1, 2, 17, FH cells
bind CD40 on B cells and innate immune cells

activate these target cells
allow DC licensing and expression of co-stimulatory molecules

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13
Q

3 signals, specific, activation methods

CD8+ T cell activation and CTL

A

signal 1: APC p:MHC class I
signal 2: CD28-B7 1.2(CD80/86)
signal 3: mainly IL-2. also IL-12

specific consideration
CD8+ cells require more co-stimulation
IL-2: autocrine and paracrine from Th1 and 17
require cd4+ t cells to help activation

two activation method
1.major: CD4 effector T cells and license DC to cross present
2.rare: directly by DC that have high costimulatory activity (DC infected by virus)

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14
Q

2 models of CD8+ T cell activation

A

1.sequential
APC licensed by effector CD4+ T cells–interact with CD8+ T cells independently
IL-2 produced by CD8+ alone induce proliferation

2.simultaneous
APC licesde by effector CD4+ T cells, interact with CD8+ T cells at same time
CD40 signaling (leads DC licensing and expression of more co-stimulatory molecules)
IL-2 secreted by both CD4+ and CD8+ T cells

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15
Q

Activation of CD4+ T cells

A

IL-2 secretion
CD40L expression

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16
Q

APC is licensed by activated CD4+ T cell through CD40 binding

A
  1. presenting exogenous antigen via MHC class II, then cross-presentation via MHC class I
  2. increase expression of CD80/86
  3. induction of additional molecule that activates CD8+T cells such as 4-1BBL (bind to 4-1BB) and CD70 to provide cosimulatory molecules along with B7
  4. increasde production of IL-2

CD4+ T cell help is critical to generate memory CD8+ T cells

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17
Q

CTL

A

CTL leaves the lymph mode and travels to the site of infection

kill infected cells in the infection site by TCR bind with pMHC class I
(all nucleated cells epcress MHC class I)

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18
Q

CTL effector function

A

-Initial interaction via nonspecific adhesion molecules
-if pMHC isn’t match, then CTL move on
-if recognized, cause death of the infected cell

Induces apoptosis to kill infected cells
- Fas-FasL
- Granules

Secrete cytokines to direct immune response

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19
Q

Fas-FasL mediated killiing

A

effector CTL expresses FasL
infected cells express Fas

FasL-Fas interaction cascade cause cleavage of procaspases to caspases, ultimately leading to apoptosis of the target cell

Fas bind FADD—–procaspase-8——caspase 8—–procaspase-3 and 7——-caspase 3 and 7

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20
Q

granule-mediated killing

A

TCR:pMHC1
reorganized cytoskeleton and cytoplasmic content (granules)
granules releases at point of cell contact

granules contain perforin and granzymes

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21
Q

perforin

A

aids in delivering contents and granules, create a pore for granzyme B to pass through the membrane go inside the cell

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22
Q

granzymes (granzyme B)

A

go into cytoplasm of the target cell
serine proteases

initiates signaling through procaspases cleavgae into caspases + other factors
activate apoptosis (DNA fragmentation and cell death)

membrane blebbing (cytoskeleton break and causes membrane to bulge out ward) is a classic sign of apoptosis

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23
Q

compare and contrast of Fas-FasL and perforin/granzyme pathway

A

same: both cleavage on various caspase 3 activation leading to apoptosis

different:
perforin/granzyme is fast acting, primarily way
Fas-FasL is slow acting mechanism

CTL lytic action enhanced when both mechanisms operate simytaneously

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24
Q

CTLs exert effect via cytokines

A

secrete IFN gama (type II IFN)

function of IFN gama:
1.increase MHC I expression in neighboring cells
2.activate macrophages and stimulates the production of chemokines that recruit macrophages

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25
type I and II IFN
type I: antiviral effects, effect of PRR activation type II: role in immune reponse against intracellulalr pathogens, secreted by CD8+ T cells
26
CD4+ T cell overview
Th1: type 1 response virus and intracellullar pathogen target macrophages Th2: type 2 response parasite like helminths and other extracellular pathogens, also allergy target eosinophil, mast cell, basophil Th17: type 3 response fungi and extracellular bacteria, also autoimmunity target neutrophil Tfh: activate B cells in lymph nodes
27
key effector molecules and cytokines of effector T cells
CTL: perforin, granzyme B, FasL, IFN gama Th1: IFN gama, CD40L, FasL Th2: IL-4, IL-5, IL-13, CD40L Th17: IL-17, IL-22, CD40L Treg: IL-10, TGF beta
28
cross regulation
**Cytokine** Th2 secrete IL-4 and IL-5, inhibit Th1 differentiation Th1 secrete IFN-gama, inhibit Th2 porliferation IL-4 or IFN-gama inhibit Th17 differentiation these cytokines help reinforce the predominant subtype thye are part of **TF** mastertranscriptional regulators commit T cells to one subset or the other T-Bet suppresses Th2 pathway gene expression GATA-3 suppresses Th1 pathway gene expression
29
decision point of Th17 and T reg
**TGF-beta**: key cytokine of differentiation of both if only TGF-beta, produce iTreg to keep inflammation down **IL-6**: switch, inducing Th17 subset differentiation IL-6 is produced after infection, Th17 to clear pathogens
30
homing of effector T cell
Th1, Th2, Th17 will leave lymph node and migrate to site of infection to clear pathogens and target other immune cells Tfh will stay lymph node and activate B cells Different cell surface molecules are expressed by naïve vs effector T cells, since they travel to different locations in the body --Effector T cells express molecules that target them specific tissues (eg. skin vs gut), depending on the site of infection Where effector T cells travel is partly determined by which lymph node they get activated (usually is the lymph node that closed to the infection site)
31
# signal 3, TF(2), effector cytokine, target cell, pathogen type Th1 cells (siganls)
signal 3: **IFN-gama and IL-12** TF: **STAT-1**(IFN-gama) and **STAT-4** (IL-12) Master transcriptional regulator: **T-bet** Effector cytokine: **IFN-gama** **Active macrophage Active CTL (thorugh CD40L binding, licensing DC to present peptide to MHC 1)** **Intracellular pathogens** (bacteria, viruses, parasites)
32
Th1 funtion (type 1 response)
1.secrete IFN-gama to site of infection 2.target M1 marcrophages, aid in killing of microorganisms that persist in macorphage vesicles 3.killing macrophages 4.produce IL-2 act on naïve CD4/8+ T cells 5.produce IL-3 and GM-CSF to stimulate production of monocytes by bone marrow 6.produce TNF-alpha act on local blood vessel: change expression of adhesion molecules on neighboring endothelium to recruit more macrophages 7.produce chemokine CCL-2 to recruit more monocytes (macrophages) to the site of infection
33
Th1 function 2 activated M1 macrophage
M1 macropahges: classically activated macrophages some pathogens persist in macrophages (inhibit fusion of phagosome and lysosome, prevent acidification that activate lysosomal proteases) Th1recognize **pMHC class II on surface, uses CD40L to bind CD40** secrete **IFN-gama** to boost macrophage antimicrobila activity and production of **TNF alpha** from the macrophage -TNF alpha: autocrine, survival signal to macrophage itself -TNF alpha and IFN-gama: **increase expression of MHC class I and II, CD40, B7, IL-12**, which further activate Th1 IFN-gama from CTL can also activate M1 macrophages
34
Th1 function 3 kill infected macrophage
chronically infected macrophages 1.recognize pMHC class II on infected macrophages 2.FasL on Th1 binds Fas on infected cells, triggers apoptosis bacteria released can be phagocytosed by freshly recruited macrophages
35
Th1 function 4 help CD8+ T cells
secrete IL-2 and stimulate CD8+ T cell proliferation and differentiation occur in the secodary lymphoid organ CTL recoognize via pMHCI binding and kill infected macrophages
36
Th1 function 5 stimulate increased differentiation of monocytes in bone marrow
secrete IL-3 and GM-CSF circulate in blood and act on precursors in the bone marrow (example of endocrine)
37
granuloma formation
core of infected macrophages surrounded by layer of activated macrophages, then layer of Th1 cells centre often become necrotic: cell die in the centre from a combination of lack of O2 and cytotoxic effect of activated macrophages
38
# signal 3, TF (2), effector cytokine, pathogen, target cell Th2 (signals)
signal 3: **IL-4** TF: **STAT-6** Master transcriptional regulator: **GATA-3** Effector cytokine: **IL-4, IL-5, IL-13** **Active eosinphil, mast cells, basophils, and macrophages** **parasites, maily helminth** **dysregulated Th2 responses are involved in allergies or asthma**
39
Th2 function (Type 2 response)
1. sometimes clear the pathogen, usually only reduce worm burndern-->cause chronic infection 2. "weep and sweep" 3. facilitate tissue repair (IL-13) 4. IgE antibodies generation (eosinophil activation) 5. recruite and activate macrophages (M2) 6. mast cell activation 7. basophil activation
40
Th2 function IL-13
promote cell turnover of epithelial tissue increase mucous production by goblet cells ("weep") stimulate smooth muscle cells to contract which enhance worm expulsion ("sweep")
41
Th2 function recruit and activate M2 macrophages
M2 macrophage: alternatively activate macrophages -**aid tissue repair** -participate in worm kiling and expulsion -form **granulomas to entrap worms** -release toxic mediators directly onto the worm by **ADCC** (antibody-dependent cell-mediatde cytotoxicity) **IL-4 and IL-13** is important for M2 macrophage activation
42
ADCC
antibody bind Fc receptor on M2 macrophages intracellular signal macrophages produce toxin toxin target parasite to kill it most ADCC is mediated by NK cells
43
Th2 function eosinophil activation
**IL-5**: activates, recruits and enhaces eosinophil differentiation eosinophil granules contain **major basic protein (MBP)**, which can kill parasites **IL-4 and IL-13 lead to IgE generation** IgE bind antigens on parasites, eosinophils express recoptors recognize Fc portion of IgE, thus allow eosinophils specifically target pathogen and degranulate to kill it IgE can be consider as a opsinin
44
Th2 function mast cell activation
IL-9 and IL-13 activate mast cell mast cell granules contain histamine and other molecules -increase vascular permeability -increase intestinal motility -increase recruitment of inflammatory cells mast cells express receptors that recognize the Fc portion of IgE, can target IgE coat parasite
45
Th2 function basophils
secrete IL-4 and IL-13 activate goblet cells, allow vasodilation bind to IgE and releases histamines
46
type 2 reponse and allergy
allergens enter the host via mucosal tissues and induce Th2 response allergies are initiated by an interaction between an IgE antibody and antigen IgE bind to mast cells or basophils induce degranulation -granules content released include histamine, proteases, chemokines -act on surrounding tissues and cells to cause symptoms healthy individual make IgE only in response to parasitic infection
47
# Signal 3, TF (2), effector cytokine, target cell, pathogen Th17 signals
signal 3: **TGF-beta, IL-6, IL-23** TF: **STAT-3** Master transcriptional regulator: **RORgama-T** Effector cytokine: **IL-17(a/f), IL-22** **Enhance neutrophil responses and mucosal immunity** **extracellular bacteria and fungi** **pro-inflammatory response and autoimmunity** ## Footnote TGF-beta phosphorylate STAT-3
48
Th17 funtion
1. IL-17 and IL-22 induce production of antimicrobial peptide by epithelial cells 2. increase epithelial turnover 3. IL17 stimulate neutrophil production in bone marrow 4. IL-17 induce production of chemokines that recruit neutrophil 5. produce chemokine CCL20 that recruit other Th17
49
Th17 function inflammation
**IL-17: pro-inflammatory cytokine** TH17 responses are involved in a number of inflammatory diseases, including autoimmune diseases - Psoriasis - Inflammatory Bowel Disease - Asthma - Rheumatoid Arthritis - Multiple Sclerosis
50
Th17 function induce production of antimicrobial peptides
IL-17 and IL-22 induce epithelial cells to produce antimicrobial peptides contribute to killing and slowing replication of bacteria
51
Th17 function increase epithelial turnover
IL-22 increase division and shedding(去除) of epithlial cell hinder bacteria growth (make bacteria hard to colonize)
52
Th17 function induces other cells to produce G-CSF
IL-17 acts on **stromal and myeloid cells** These cells secrete G-CSF (endocrine cytokine, also secreted by Th1) G-CSF enters circulation and targets bone marrow precursors to differentiate into neutrophils
53
Th17 function induce other cells to secrete chemokines
IL-17 acts on stromal and epithelial cells these cells secrete chemokines chemokine attract neotrophils
54
neotrophils function
phagocytosis form NETs release granules that can kill bacteria and fungi
55
Th17 function other effect
IL-17 can induce macrophages to secrete pro-inflammatory cytokines such as IL-1beta and TNF-alpha TH17 cells have several different proinflammatory effects
56
autoimmunity
IL-17 targeted using **monoclonal antibodies** * A monoclonal antibody: antibodies produced by a single clone of B lymphocytes, so that they are all identical - Bind specifically to target to either activate or inhibit its activity Two approaches to targeting IL-17 in psoriasis using antibodies: - **IL17-receptor antagonist** (blocks signaling from the IL-17 receptor) - **Anti-IL-17 neutralizing antibodies** (binds to IL-17 and prevents it from interacting with receptor)
57
ILC and T cell
ILCs are activated by cytokines and different group target different pathogens Example: **ILC2 and TH2 cells** produce a trio of cytokines,**IL-4, IL-5, and IL-13** - Generate IgE and degranulation of granulocytes and other functions that can kill and clear helminth infection Example: **ILC3 can cooperate with Th17**and **produce IL-17** to defend against bacterial infection
58
# signal 3, TF (2), effector cytokines, pathogen, target cell Tfh cell (signal)
signal 3: **IL-6** TF: **STAT-3** Master transcriptional regulator: **Bcl-6** Effector cytokine: **IL-21(activate B cells), other cytokine depends on which type of pathogen and response** (IFN-gama for 1, IL-4 for 2, IL-17 for 3) **Activate B cells in lymph nodes** **respond to all type of pathogens**
59
NKT cells
lymphoid lineage -express TCR, bind with **lipid and glycolipid peptides on CD1** -developed in thymus -antigen receptor gene reaarangment but not as diverse as T cells -releases cytotoxic granules that kills target cells and releases large quantities of cytokines -kill target cells (express activating and inhibitory receptors) -donot form memory cells
60
CD1
similar structure with MHC class 1 lipid antigen-binding groove instead of peptide
61
negative regulation
involves receptors, mechanisms, and cell types The immune response contracts within 10–14 days - After Ag is removed, most lymphocytes are no longer required and undergo apoptosis - Treg cells may also help to quell responses by releasing inhibitory cytokines
62
clonal contraction
about 2 weeks: most newly generated B and T cells are lost at the end of the primary immune response (after Ag is cleared, most of the effector cells are no longer required) cell die by apoptosis
63
intransic pathway of apoptosis
* “Death by neglect” * IL2R-alpha and other cytokine receptors expression is transient (impermanent) -IL2R-alpha is also a survival signal * Lack of signaling through these receptors → absence of survival signal → apoptosis
64
extransic pathway of apoptosis
involve CTL tiggered by Fas (on T cell)-FasL (on CTL) leads to apoptosis
65
memory T cells
majority (~90%) effector T cells die leaving behind antigen-specific memory T cells Memory cells respond with **heightened reactivity to a subsequent exposure to the same antigen** - The secondary response is **faster and more robust → more effective**
66
Inhibitory/Regulatory Receptors
CTLA-4 PD-1
67
**CTLA-4**
**Down-regulates T cell activation, proliferation, survival** **Binds to B7.1/B7.2**with higher affinity than CD28 and shuts down signaling pathways, preventing excessive and uncontrolled immune responses Induced within 24 hours after T cell activation, peaks 2–3 days post-stimulation **CTLA-4 found intracellularly** → *phosphorylation* allows it to be expressed on the cell membrane ( **example of Post-translational regulation**) 1 CTLA-4 molecule can bind 2 B7 molecules -binding sequesters B7 and prevents binding to CD28 -CTLA-4 in some cases can strip B7 molecules from antigen-presenting cells and remove them from APC surface Surface expression of CTLA-4 is induced after activation of naïve T cells (after receiving signals 1 and 2) - Making activated T cells less sensitive than naïve T cells to stimulation by APCs and restricting IL-2 production - Prevents overgrowth of lymphocytes
68
PD-1
PD-1 can be expressed on activated T cells - Binds **PDL-1 (expressed by many cells) and PDL-2 (on APCs during inflammation)** - PD-1 signaling down-regulates T cell activation/proliferation and function - **Marker of T cell “exhaustion”** → occurs in chronic diseases - Blocking PD-1 or PDL-1 or even CTLA-4 are targets of some cancer therapies
69
# signal 3, effector cytokine, TF(2), target cell iTreg (signal)
i: induced (arise in the lymph node) signal 3: **IL-2 and TGF-beta** TF: **STAT-5** Master transcriptional regulator: **FoxP3** Effector cytokine: **IL-10 and TGF beta (anti-inflammatory cytokine)** **Suppresses immune responses, specifically maintain immune tolerance to self-antigens (prevent autoimmunity)** **represses other immune cells, mainly T cells**
70
Treg subsets
**natural T regs** - **Thymus-derived** - Selected for **high affinity for self peptides** → but to dampen (抑制) the immune response to them! - Express**TCR, CD4, IL2R alpha, and CTLA-4** - They are **unable to provide IL-2**so they rely on other cells - Express FoxP3 **induced (adaptive) T reg** - Arise in the periphery from CD4+ T cells - Express TCR, CD4, IL2R-alpha, and CTLA-4 - Express FoxP3 (some exceptions)
71
Treg function
deplete (耗尽) local area of stimulating cytokines - express IL2R-alpha (CD25) chain to take IL-2 B7 sequestration by CTLA-4 (express by Treg) - inhibit APC activity by reducing co-stimulatory molecule expression and proinflammatory cytokine secretion - reduce T cell differentiation and activation produce immunosuppressive cytokines (IL-10 and TGF-beta) directly kill T cells through granzymes and metabolic disruption
72
Treg mechanism
**IL-10:** inhibit production of **Th1 and Th17 cytokines** **TGF-beta:** inhibits T cell proliferation and inhibit the development and function of **Th1 and Th2** Tregs are specific to peptides that are self or safe non-self - nTreg recognizes self-peptide:MHC → arises in thymus - iTreg recognizes peptide:MHC (could be self or commensal Ag) → arises in periphery Majority of autoreactive T cells are deleted in the development process in the thymus - Some of these T cells can escape and can cause allergies or autoimmunity
73
when Treg recognize autoreactive T cell
Treg recognizes a APC presenting self-peptides T regs secrete cytokines that will inhibit neighbouring (potentially autoreactive) T cells that recognize other self-peptides:MHC being presented by the same cell from getting activated

MIMM 214 (6 decks)

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