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IL-2
First signal
=CTLPrecurseurs
Molécules effectrices des Lymphocytes cytotoxiques T (CTL)
Solubles
Cytokines : INF-g, TNF-b
Cytotoxines : Perforine
Granzyme
Membranaires
Ligand de Fas
La cytolyse
CTL
TCR
HLA Cl1
cible
Microtubules
Golgi
apoptose
The control of
intracellular proteins
by MHC Cl I molecules
Cytoplasmic
Foreign protein
killing
CTL deleted
The control of
Or
intracellular proteins tolerized
No killing
by MHC Cl I molecules
Self - protein
Mediators of NK cells functional effects
Tumor
or virus infected
cells
Direct lysis
Perforine /granzyme
Cytokine secretions : INFg +++++
TNFa+++
GMCSF+++
Chimiokines : CCL4, 5 & 22
Cytotoxycité des NK( anti virale ou
anti-tumorale) déclenchée par
le « soi manquant »
Famille des KIRs (Killer Ig like Receptors)
: Exprimés chez les primates ; gènes regroupés sur le chromosome 19
(= leucocyte receptor complex, 150 Kb)
Monomères, homo et hétérodimers (14 molécules connues chez l’homme)
Ligands : molécules HLA de classe I : contact sur les hélices alpha des
poches à peptide, sur quelques résidus seulement
=> spécificité pour un
sous type de HLA I (Exemple de spécificité : KIR2DL2 peut se lier à HLA-Cw1,
w3, w7 et w8.KIR3DL1 à bw4 )
KIRs inhibiteurs (long tailed)
KIR activateurs (short tailed)
Molécule DAP 12
KIR2DL
KIR3DL
Domaine ITIM
KIR2DS
domaine ITAM
KIR, TCR and HLA-Cl1
Intracellular modules of immunological
receptors
Activator = ITAM : …..ILVxxYLV…..
(ex : CD3 chains, syk kinases
NK activs.)
Inhibitor = ITIM
: …..YxxLx…..Yxxl…
(ex : SHP & SHIP, NK inhibs.)
Famille des lectines de type II, (Ly49) :
exprimée chez les rongeurs
Ligands : résidus sucrés des molécules HLA de classe I
Inhibiteurs
ITIM
Activateurs
Se lie probablement à une
Molécule de type Dap 12
Homodimers ; genes located on mouse chr. 6
=> NKC gene complex
Famille des lectines de type C
: exprimée chez les rongeurs et les primates
Inhibiteurs
activateurs
Heterodimers (2° chaine = CD94)
CD94
DAP12
ITIM
ITAM
Gènes sur le complexe NKC (chr. 6 souris; 12 primates)
Lient HLA classiques
The C-lectin like NKG2D
Homodimer ?
Dap10
Activators : The NKp family
• 3 Ig superfamily members distincts from KIRS
• Specific for NK cells
• Charged residues in TM segment => module association
•CD3zeta,, FcERIg, DAP12…
Receptor
NKp30
NKp46
NKp44
adaptor
FCeRIg or CD3z
FCeRIg or CD3z
Dap 12
ligand
?
influenza HA,…
influenza HA,…
Central role in Nk cell mediated killing of cancer cells
NKc mediated killing of viral cells blocked by anti - HA
NK cells express three types of receptors:
activating, inhibitory and co-stimulatory
receptors.
Target cell
NK cell
NK cell activities : a delicate balance
Interacting cell
Bacterial or viral product
Activating receptors
Inhibitory receptors
Inhibitory module
= ITIM :
…..YxxLx…..Yxxl…
Activator module
= ITAM :
…..ILVxxYLV…..
Syk kinases
MHC molecules
NK cell
SHP & SHIP Pases
Organization of the KLR Locus
Genomic structure of lectin-like
receptors encoded in the natural killer
gene complex.
Inhibitory NK receptors for MHC
Activating NK cell receptors and their ligands
Activating receptors and their
intracellular modules
NKG2D et les infections virales :
Pour contrarier les virus
Cellule inféctée
Par HCMV
Ly49h : Un recepteur activateur qui renforce
les défenses anti-CMV
Cellule inféctée par MCMV
m157
Les protéines de stress et les NK
Stress ; transformation maligne
NK cells D cells cross-talk in tissues
NATURAL KILLER CELLS AND DENDRITIC CELLS:
RENDEZVOUS IN ABUSED TISSUES
Dendritic cells are equipped to ingest
living, apoptotic and necrotic cells
Immune complexes
Toll R
FcR
Osponized
live or dead
cells
CR3/4
PSR
CD36
CD91 aVb5
Apoptotic cells
Necrotic
cells
Priming NK Cells
< previous nex
t>
NK cells differentiation I
NK Cell
differentiaton 2
KILLER?
NK cells
in vitro
>
KIR
HLA-class I specificity
KIR2DL1
Group 2 HLA-C alleles expressing Lys80 (such as, HLA-Cw2, -Cw4, -Cw5, Cw6)
HLA-class I allele specificity of the main inhibitory KIR.
KIR2DL2/3
Group 1 HLA-C alleles expressing Asn80 (such as HLA-Cw1, -Cw3, -Cw7, Cw8)
KIR3DL1
HLA-Bw4 alleles (e.g. HLA-B27)
Donor NK cell allospecificity for ‘missing self’ on recipient targets.
Mismatch KIR lors d’une greffe
hématopoïétique haplo-identique
Farag et al, Blood 2002
Kaplan-Meier estimates of the probability
of leukaemia relapse of 40 high-risk AML recipients
Kaplan-Meier estimates of the probability
of survival of 40 high-risk AML recipients
Two types of memory T cells
Blood to lymph nodes
CD62L +++
CCR7 +
CD2945RA-O+
CD62L +++
Stay in LN
Goes to
Inflammatory area
CCR7+
CD29+++
45RA+,ROCD62L CCR7CCR5, 4, 2 et
3 high
CD29+++
45RA+,RO-
virgin
Ag stimulation
Central
memory
Ag stimulation
Effector
memory
T cell exhaustion during chronic viral infection
R
e
Reinvigorating
Exhausted T Cells
i
Freeman GJ JEM, sept 06
n
v
i
Resolved
g
Infection
o
r
a
t
i
n
g
Chronic Infection