Chap 7,10 Cytokine and Cell mediated cytotoxicity

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Chap 7,10Cytokine and Cell mediated
cytotoxicity
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Cytokine

• A small protein that usually act in an autocrine
  or paracrine manner
• Highly-regulated
• Little dose exert dramatic effects (eq. INF)
• gt200 types of cytokines in human
• Act by binding to cell surface receptor
• gtinduction of signal transduction cascade
• gtaffect gene expression
• Multiple functions (eq. IL-6)
• Redundancy in the role of immune system

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1 picogram of INF survive the whole cell lines
from virus killing (left or right ?)
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Nomenclature reflect first-described function and
order of discovery
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• Multiple functions of cytokine

IF-6 sti osteoclast formation especially after
estrogen depletion
OR TNF-alpha (p.120)
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4 types of cytokine receptor (by structural
difference)
Ig homologue
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Signaling
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Engagement of cytokine receptors activates
intracellular signaling pathway
Ligand induced R aggregation
?????promoter region
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Receptor between IL-2 and IL-4

• FIG 7.7

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MOST TYPE I receptor of the cytokine receptor
superfamily are associated with Janus kinase
(Jaks)

• Phosphorylated activation (on tyr of two Jak
  kinase) after aggregation of receptor by ligand
  binding
• Jak activation is required for MOST receptor
  function
• Dimerized phosphorylated-stat can translocate
  into nucleus, act as TF
• Unique cytokine function reflect different
  intracellular signal pathway
• Other pathway existed
• TNF-a sti MAP kinases, resulting in activation of
  TF (eq. AP-1?NF-kB)

?
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TNF signaling

• Fig 7.11

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Typical protein induced by cytokine
(????)
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Cytokine v.s. Th
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Cytokine regulating Th subsets development

• Th1 mediate macrophage activation
• Th1 cytokine include TNF-b, IFN-g,IL-3, IL-12
• Th2 mediate antibody production and allergy
• Th2 cytokine include IL-4,,IL10

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Interaction of Th1 Th2

• Different protective role of Th1/Th2
• Cytokine from Th1 inhibit the action of Th2 and
  vice versa
• Immune response tends to settle into Th1-type
  response or Th2-type
• Common examples
• Allograft Rejection, multiple sclerosis_____
• Asthma (by pollen), SLE_____

TH1
TH2
????????? ??????? //?? (homework!)
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• Factor that influence Th1/Th2 decision
• Cytokine profiles
• IL-4 favor Th2 IL-12 favor Th1
• Antigen dose
• APC
• Host genetic background
• Activity of co-sti molecules and
• hormones in the environment
• Cortisol (stress induced) tends to Th2 induction

(vessel or tissue ? Ab or ma?)
(MOST viral glycoprotein favor Ab)
Grain induced ma in NORMAL pts not IgE
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T cell-independent defensephagocytosistriggerin
g cytokine release
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1. Phagocytosis 2. trigger cytokine release per
se
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Phagocytosis

• Chemotactic by Ab, Complements, common microbe
  component
• T cell independent defense

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Triggering cytokine release

• All invading organism contain molecules ready to
  trigger cytokine release.
• For example, LPS is the most potent cytokine
  inducer

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Cytokines in early immune response

• TNF-a, IL12,IL-1 release by macrophage is
  essential for early immune response
• Three fundamental function
• Supply signal to endothelial cells that initiates
  recruitment of WBC
• Activate phagocyte within tissues while T cell
  immune is under-developed
• Provide signals to decide Th1/Th2 pathway

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Cytokine is essential for WBC recruitment

• ROLLING TNF-a, IL-1, LPS induce the expression
  of E-/P-selectin on endothelial cells
• Adhesion TNF-a, IL-1 induce iCAM-1 expression
  which bind to integrin on WBC
• Tethering Chemokine (eq. MCP-1) attach
  endothelium and trigger tethering of WBC

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REGULATING cytokine
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Chap 10.Cell-mediated cytotoxicity
Tc
NK
????
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Complementary element for viral immunity
FcR
ADCC
If NK receptor recognize AB on target cells, the
cytotoxicity means ________
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Central Organizing role Th cells

• Appropriate effector mechanism must be selected
  for each infection targets.
• inappropriate effector mechanism enhanced
  susceptibility
• Eq HIV infection, macrophage activation BAD
  Activate Tc GOOD
• Three pattern of effector mechanism
• Cytotoxicity mediated by Tc cells or LGL (NK)
• Macrophage activation by Th1
• Antibodies production by B cells directed by Th2

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Cell-mediated cytotoxicity

• Cell-mediated cytotoxicity is an essential
  defence against INTRACELLULAR pathogens.
• Effector cells Tc, NK, sometimes myeloid cells
• Tc and NK recognize their targets in different
  ways.
• Tc recognized Ag presented with MHC by TCR
• 90 Tc express CD8, which bind with class I MHC
  (expressed by ????????)
• 10 Tc express CD4, which bind with class II MHC
• Function Elimination of cells infected with
  virus.
• NK recognized Ag failed to presented with MHC by
  NK receptor
• NK receptor included eq. CD16 (bind Ab-coated
  Ag), execute ADCC
• Tc and NK are complementary against
  virus-infected cells
• ????????????Tc?Class I MHC???(?????????????),?????
  ?,???NK?????????

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Additional interaction required to stablize Tc
cell and the target cells
Physical binding of CD2 (for example, Anti-CD2
Ab) trigger cytotoxity induced by TC cells
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MHC class I molecules inhibit NK-cell-mediated
cytotoxicity

• MHC class I (HLA-A, HLA-B, HLA-C loci) inhibit NK
  cytoxotic activity
• ??NK??????
• HLA-G (dominant NK inhibitor) expressed on
  placental trophoblast cells
• trophoblast cells (from Fetus) is allogenetic to
  mother.
• HLA-G provide protection to the placenta from
  attack by NK
• ?????NK??????

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KIR (killer inhibitory receptor) CD94 NKG2
family NKG2 family consisted of 6 NKG2A to
NKG2F Decide the activity of KIR Ie NKG2A
?ITIM ?????? Ie NKG2C ??ITIM ???????
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HLA-E Ligand for KIR Present leader peptide of
MHC class I to KIR Cells lacking MHC class I
cannot present leader peptide and cannot
inhibit NK A good device for monitoring the
presence or absence of MHC Class I in a cells
infected by a virus
CLASS I???, ??leader peptide ?HLA-E??, ??peptide
??? CLASS I
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Just REF
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Cell-mediatedcytotoxicity
CHAP 7
Mechanism
????
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3 Mechanism of cytotoxicity

• Direct cellular interactions
• Cytokines
• granule exocytosis

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granule exocytosis

• Granules contains perforin and granzymes
• Perforin pore-forming protein, like C9 complex
• Ca and serine esterase enhance polymerization
  of perforin at target mem
• Proteoglycan (Chindroitin sulphate ) prevent
  autodestruction at Tc/NK mem
• granzymes a collection of serine esterase
• Activated after releasing
• Not essential for cytotocixity
• Interact intracellularly to trigger APOPTOSIS

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Peptide chain
Serine
Serine esterase
P
Serine
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Direct cellular interactions Cytokines
release

• Perforin-independent killing pathway exist
• CD4 Tc (without perforin) still can lyse target.
• Cell-death receptor Fas (CD95) and TNF receptor
• Wild spread on all cells
• Direct apoptosis
• Structurally similar (with intracellular DEATH
  domain)
• FasL (Ligand for Fas)
• Expressed on matured CD4 CD8 T cells
• Inducing clustering of Fas
• TNF-a or TNF-b
• Released by Cytotoxic T-cell vesicle
• Killing mechanism
• CD8 Tc By FasL, granules (TNF, perforin)
  release
• CD4 Tc By FasL
• NK By granules (TNF, perforin) release

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Killing mechanism of Myeloid cells
In addition to cytokine-mediated attack, myeloid
cells release above mediators which act
synergistically in the killing of target
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Role of macrophage
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Macrophage

• Be involved in all stage of immune response
• Rapid protective mechanism (response before T
  cell amplification)

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7 roles in Macrophage

• Be essential in the effector phase of
  cell-mediated response

????????
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Macrophages are heterogeneous

• Activated macrophage show enhanced ability to
  kill some microorganisms, not not other.
• Heterogeneous due to (most acceptable concept)
• Environmental , maturational effects, different
  cytokines, inflammation sti

activated Macrophage
resting Macrophage
activated Macrophage
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Macrophage activation

• Required sequential (step by step) stimuli
• Sometimes, more than one signal is required to
  elicit a particular function
• In mouse, to produce NO (toxic for tumor and
  bacteria), macrophage need to be sequentially
  stimulated by
• (1) INF-g
• (2) TNF-a
• In human, NO production by macrophage is
  highly-regulated
• Several cytokine involved
• Cross-linking of FceRII

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Positive/Negative activation

• Negative regulator
• Prostaglandin E
• MDF (macrophage deactivating factor)
• Blocking INF-r signal pathway
• IL4
• TGF-b

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Calcitriol regulate macrophage activation and
Th1/Th2 balance

• INF-stimulated Macrophage express 1-a-hydroxylase
  which induce converting of active calcitriol
• Calcitriol (or Vit D3)
• Responsible for amplification loop of Macrophage
• Powerful negative feedback on Th1
• ????????????(????)
• Shift Th1 -gt Th2

Circulating inactivated
autocrine loop
_
Macrophage activation
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THANX FOR URATTENTION
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