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Cross-talk among M , NK and cancer cells:

Cross-talk among M , NK and cancer cells: M  cells help NK cells to attack tumor by stimulatory RAE-1 but escape from NK killing by inhibitory Qa-1 Zhigang Tian, Zhixia Zhou, Cai Zhang (tzg@ustc.edu.cn). Institute of Immunology/School of Life Sciences

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Cross-talk among M , NK and cancer cells:

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  1. Cross-talk among M, NK and cancer cells: M cells help NK cells to attack tumor by stimulatory RAE-1 but escape from NK killing by inhibitory Qa-1 Zhigang Tian, Zhixia Zhou, Cai Zhang (tzg@ustc.edu.cn) Institute of Immunology/School of Life Sciences University of Science & Technology of China Chinese Academy of Sciences Hefei, Anhui, China August 19, 2010, Shenzhen

  2. Figure 2-49 NK cell: a professional killer of tumor

  3. NK Cell Immunological Synapse Nature review immunology, 2008;8:713 Three main stages of cell lytic synapse 1.initiation 2.effector 3.termination Two kinds of immunological synapse SMAC: supramolecular activation cluster SMIC: supramolecular inhibitory cluster

  4. NK Cell Immunological Synapse Nature review immunology, 2008;8:713

  5. Natural killer cell recognition of “missing self” Annu. Rev. Immunol. 2005. 23:225–74

  6. KIR :killer immunoglobulin-like receptors KLR:killer lectin-like receptors

  7. NK M 1. Macrophages increase cytolysis of NK cells against cancer cells Poly I:C Untreated peritoneal M poly I:C treated peritoneal M 6 5 4 % Lysis of NK cells to M  3 2 + 1 0 50:1 25:1 5:1 E/T ratio NK alone 90 ** NK/M (medium) 80 NK/M (poly I:C) 70 60 * 50 % Lysis of NK cells to tumor Tumor cells 40 * 30 20 10 0 5:1 25:1 50:1 Death E/T ratio

  8. 6 5 NK + RAW264.7 NK + RAW264.7 (poly I:C) NK only * 4 3 Fold Induction of NKG2D gene 36.48% 32.74% 50.71% 2 1 0 NKG2D NK alone NK + RAW264.7 NK + RAW264.7 (poly I :C) NK M 2. Poly I:C-treated macrophages increase NKG2D expression of NK cells Poly I:C NKG2D ㈩ ㈩ Events Tumor cells Death

  9. NK + M(poly I:C) + Isotype-control NK + M(poly I:C) + anti-NKG2D NK + M (poly I:C) NK + M NK only 25.71% 25.13% 62.52% 55.03% 38.41% Events CD69 NK alone NK NK+MØ NK+MØ (poly I:C) NK+MØ (poly I:C)+Isotype-contyol M NK+MØ (poly I:C)+ anti-NKG2D 25 * 20 15 Fold Expression * * 10 5 0 FasL Perforin TRAIL 3. Increased NKG2D expression correlates to activation of NK cells Poly I:C NKG2D ㈩ ㈩ Tumor cells Death

  10. MØ alone MØ(poly I:C) NK NK alone * NK+MØ NK+MØ(poly I:C) M NK+MØ (poly I:C)+Isotype-contyol NK+MØ(poly I:C)+anti-NKG2D 80 * M(Medium) * M(poly I:C) 700 M(poly I:C)+Isotype-control 60 600 M(poly I:C)+Anti-NKG2D % Lysis to YAC-1 cells 500 * 40 400 IFN-(pg/ml) 300 20 200 100 0 5:1 25:1 50:1 E:T ratio 4. Increased NKG2D expression correlates to function of NK cells Poly I:C IFN-g NKG2D ㈩ ㈩ IFN-g Tumor cells Death

  11. ** Untreated M 500 poly I:C treated M 450 400 350 300 pg/ml * 250 * 200 150 * 100 50 0 IFN- IL-18 IL-15 IL-12 IFN- NK M 5. Macrophage-derived cytokines play critical roles in NK cell activation Poly I:C IFN-g NKG2D IL-15 IFN- IL-12 IL-18 ㈩ NK NK NK M (poly I:C) M (poly I:C) M (poly I:C) NK ㈩ IFN-g NK alone NK+M Isotype anti-IFN- anti-IL-15 M (poly I:C) 32.03% 40.24% 54.79% 47.80% 31.05% 22.08% Tumor cells Events NKG2D Death

  12. NK NK+ M NK+ M (poly I:C) M alone NK+ M (poly I:C)+Isotype-control NK alone M NK+ M (poly I:C)+ anti-IFN- NK+ M NK+ M (poly I:C)+ anti-Il-15 NK+ M (poly I:C) NK+ M (poly I:C)+Isotype-contyol 70 NK+ M (poly I:C)+ anti-IFN- 60 NK+ M (poly I:C)+ anti-Il-15 * 50 350 * * 300 40 * 250 % Lysis to YAC-1 cells * 30 IFN-(pg/ml) 200 20 / 150 100 10 50 0 50:1 25:1 5:1 0 E/T ratio 6. Macrophage-derived cytokines play critical roles in NK cell function Poly I:C IFN-g NKG2D IL-15 IFN- IL-12 IL-18 ㈩ ㈩ IFN-g Tumor cells Death

  13. 0 µg 10 g/ml(polyI:C) Untreated peritoneal M ** 20 g/ml(polyI:C) poly I:C treated peritoneal M 12 100 g/ml(polyI:C) 16 ** ** 10 14 12 ** ** 8 Fold Induction 10 ** Fold Induction 6 * 8 * * 6 4 * * 4 2 2 0 0 RAE-1 H60 MULT-1 RAE-1 H60 MULT-1 0 g/ml 10 g/ml 20 g/ml 100 g/ml NK 27.99% 35.98 % 53.35% 63.76% Events RAW M 1.87% 10.69% 35.85% 63.77% Events C57BL/6 0.89% 16.78% 33.85% 74.76% Events BALB/c RAE-1 7. Up-regulation of NKG2D ligands on poly I:C-treated macrophages Poly I:C IFN-g RAE-1 IL-15 IFN- IL-12 IL-18 NKG2D ㈩ ㈩ IFN-g Tumor cells Death

  14. Untreated MØ poly I:C treated M 20 ** 16 12 Fold Induction 8 4 0 TLR3 TLR4 0 µg NK 100 µg poly I:C 100 µg poly I:C+si-Control M 100 µg poly I:C+si-TLR3 * * * 6 5 4 Fold Expression 3 2 1 0 RAE-1 MULT-1 H60 8. TLR3 mediates the up-regulation of NKG2D ligands by macrophages Poly I:C IFN-g RAE-1 IL-15 IFN- IL-12 IL-18 NKG2D ㈩ ㈩ IFN-g Tumor cells Death

  15. YAC-1 YAC-1 BALB/c M BALB/c M BALB/c M +poly I:C BALB/c M +poly I:C RAW264.7 RAW264.7 RAW264.7+poly I:C RAW264.7+poly I:C 18 ** 0.09 ** 0.08 14 ** 0.07 Fold Induction 4 0.06 Relative Expression 0.05 0.04 ** 2 0.03 0.02 ** ** ** ** ** 0.01 0 0 Qa-1b Qa-1a MULT-1 H60 RAE-1 NK M NK + RAW264.7 (poly I:C) NK + RAW264.7 NK only 44.13% 37.43% 36.56% Events NKG2A 9. Qa-1 contributes to protect macrophages from NK cell-mediated lysis Poly I:C IFN-g Qa-1b RAE-1 NKG2A IL-15 IFN- IL-12 IL-18 NKG2D ㈠ ㈩ ㈩ IFN-g Tumor cells Death

  16. No treatment poly I:C * untreated * poly I:C+si-Control 60 poly I:C+si-Qa-1 poly I:C 50 poly I:C+Isotype-control 50 poly I:C+anti-Qa-1b * 40 40 * NK % Lysis to RAW264.7 % Lysis to RAW264.7 30 30 * 20 M 20 10 10 0 5:1 25:1 50:1 0 50:1 25:1 E/T ratio E/T ratio 10. Qa-1 knock-down cause macrophages sensitive to NK cell killing Poly I:C IFN-g Qa-1b RAE-1 NKG2A IL-15 IFN- IL-12 IL-18 NKG2D ㈠ ㈩ ㈩ IFN-g Tumor cells Death

  17. NK M Cross-talk among M, NK and cancer cells Poly I:C M cells help NK cells to attack tumor by RAE-1 but escape from NK killing by Qa-1 Conclusion Macrophages may activate NK cells to attack tumor by activating RAE-l-NKG2D recognition but protect themselves from cytolysis of NK cells via preferential inhibitory Qa-1-NKG2A recognition, by which the NK cells will constitutively be activated by macrophages to keep strong innate immunity against tumor. IL-15 IFN- IL-12 IL-18 IFN-g RAE-1 Qa-1b NKG2A NKG2D ㈠ ㈩ ㈩ IFN-g Tumor cells Death

  18. We Need Immunity We Enjoy Immunology

  19. “STONE MONKEY” : WELCOME YOU TO HUANG-SHAN MOUNTAIN

  20. NK receptor complex-ligand interactions

  21. Klas Kärre in the laboratory at the Karolinska Institute in 1983. Natural killer cell recognition of missing self The idea that NK cells can distinguish aberrant cells by recognizing ‘absence of the expected’, rather than ‘presence of the unexpected’ emerged more than 25 years ago. Klas Kärre recapitulates how the idea took shape, and the first five years of experimental work to test its general predictions. Nature immunology, 2008;9:477

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