IL-2 First signal =CTL- Precurseurs

Molécules effectrices des Lymphocytes cytotoxiques T (CTL) Solubles Membranaires Cytokines : INF-g, TNF-b Ligand de Fas Cytotoxines : Perforine Granzyme

La cytolyse TCR HLA Cl1 CTL cible Microtubules Golgi apoptose

The control of intracellular proteins by MHC Cl I molecules killing Cytoplasmic Foreign protein

The control of intracellular proteins by MHC Cl I molecules CTL deleted Or tolerized No killing 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 KIR2DS   Domaine ITIM domaine ITAM

CLOSE 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.)

Inhibiteurs Activateurs Famille des lectines de type II, (Ly49) : exprimée chez les rongeurs Ligands : résidus sucrés des molécules HLA de classe I Inhibiteurs Activateurs Se lie probablement à une Molécule de type Dap 12 ITIM 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 non

The C-lectin like NKG2D Dap10 Homodimer ?

CLOSE                                    

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 adaptor ligand NKp30 FCeRIg or CD3z ? NKp46 FCeRIg or CD3z influenza HA,… NKp44 Dap 12 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 MHC molecules Activating receptors Inhibitory receptors Inhibitory module = ITIM : …..YxxLx…..Yxxl… SHP & SHIP Pases Activator module = ITAM : …..ILVxxYLV….. Syk kinases NK cell

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 ED TISSUES < previous  next > NK cells D cells cross-talk in tissues

NATURAL KILLER CELLS AND DENDRITIC CELLS: RENDEZVOUS IN ABUSED TISSUES < previous  next >

Dendritic cells are equipped to ingest living, apoptotic and necrotic cells Immune complexes Osponized live or dead cells Necrotic cells Toll R FcR CR3/4 PSR CD36 aVb5 CD91 Apoptotic cells

CLOSE Priming NK Cells

NK cells differentiation I                                                                  < previous  next > NK cells differentiation I

NK Cell differentiaton 2

NK cells in vitro AT DOES IT TAKE TO MAKE A NATURAL KILLER? < previous  next > NK cells in vitro

HLA-class I specificity KIR HLA-class I specificity KIR2DL1 Group 2 HLA-C alleles expressing Lys80 (such as, HLA-Cw2, -Cw4, -Cw5, -Cw6) KIR2DL2/3 Group 1 HLA-C alleles expressing Asn80 (such as HLA-Cw1, -Cw3, -Cw7, -Cw8) KIR3DL1 HLA-Bw4 alleles (e.g. HLA-B27) HLA-class I allele specificity of the main inhibitory KIR.

Donor NK cell allospecificity for ‘missing self’ on recipient targets.

Mismatch KIR lors d’une greffe hématopoïétique haplo-identique Farag et al, Blood 2002 (A) In this example, donor and recipient are HLA haplotype–mismatched and are KIR-epitope mismatched at the HLA-C locus. The donor NK cell clones expressing KIR2DL1 recognize and are inhibited by an epitope shared by the group 2 HLA-C alleles (HLA-Cw2, 4, 5, and 6). The recipient’s leukemic blasts express HLA-Cw3, a member of the group 1 HLA-C alleles, and are, therefore, not recognized by the donor’s KIR2DL1, and activation of donor NK cell occurs with leukemic cell lysis. (B) Here, donor and recipient are haplotype-mismatched, but express HLA-C alleles of the same supertype group 2 (HLA-Cw2, 4, 5, and 6). Therefore, donor NK cell clones expressing the inhibitory KIR2DL1 recognize a “selfepitope” (HLA-Cw4) on the recipient’s cells with inhibition of lysis of leukemic blasts. KIR epitope mismatching exerts another level of graft alloreactivity and a potent GVL effect.

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 virgin CD62L +++ CCR7 + CD29- 45RA-O+ Blood to lymph nodes Ag stimulation CD62L +++ CCR7+ CD29+++ 45RA+,RO- Central memory Stay in LN Ag stimulation CD62L - CCR7- CCR5, 4, 2 et 3 high CD29+++ 45RA+,RO- Goes to Inflammatory area Effector memory

T cell exhaustion during chronic viral infection

Reinvigorating Exhausted T Cells Freeman GJ JEM, sept 06 Resolved Infection Chronic Infection