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NK cells are part of the innate immune response

NK cells are part of the innate immune response. Early response to injury and infection. Natural Killer (NK) Cells. Functions:. Cytolysis: killing infected or damaged cells Cytokine production: IFN , GM-CSF, TNF. Control of the switch from innate to adaptive immunity

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NK cells are part of the innate immune response

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  1. NK cells are part of the innate immune response Early response to injury and infection

  2. Natural Killer (NK) Cells Functions: • Cytolysis: killing infected or damaged cells • Cytokine production: IFN, GM-CSF, TNF • Control of the switch from • innate to adaptive immunity • interaction with dendritic cells • Reproduction • intrauterine NK cells • establishment of the placenta • tissue remodeling • Allogeneic hematopoietic cell transplantation • mediate graft rejection • mediate graft vs leukemia (GVL) • prevent graft vs host disease (GVHD) • Control of infection • particularly virus infections

  3. Action of NK Cells is Mediated by a Balance of Inhibitory and Activating Receptors Inhibitory Receptors Activating Receptors Tolerance to self Responsiveness to pathogens KIR2DL KIR3DL LIR/ILT NKG2A LAIR NKP-R1 KIR2DS KIR3DS LIR/ILT NKG2C/E NKG2D NKR-P1 NKp30 NKp44 NKp46 NKp80 2B4

  4. Ligand Receptor 2DL1 HLA-Clys80 2DL2 HLA-Casn80 2DL3 HLA-Casn80 2DS1 HLA-Clys80 2DS2 2DS3 KIR 2DS4 2DS5 2DL4 HLA-G 2DL5 3DL1 HLA-B 3DL2 HLA-A 3DL3 3DS1 CD94 HLA-E NKG2A Lectin-like receptors CD94 HLA-E NKG2C NKG2E Human KIR and CD94:NKG2A Receptors for HLA Class I

  5. KIR Haplotype Diversity 19q13.4 Group A Haplotypes 3DL3 2DL3 2DL1 2DL4 3DL1 2DS4 3DL2 Group B Haplotypes 3DL3 2DL3 2DL1 2DL4 3DS1 2DL5A 2DS5 2DS1 3DL2 1 2DS1 3DL2 3DL3 2DL3 2DL5B 2DS3 2DL1 2DL4 3DS1 2 3DL3 2DS2 2DL2 2DL4 3DL1 2DS4 3DL2 3 3DL3 2DS2 2DL2 2DL5B 2DS3 2DL1 2DL4 3DS1 2DL5A 2DS5 2DS1 3DL2 4 . . Inhibitory KIR . Activatory KIR

  6. KIR Genotype Variation in a Panel of Individuals Donor ethnicity 3DL3 2DL3 2DS2 2DL2 2DL5 2DS3 2DL1 2DL4 3DL1 3DS1 2DS4 2DS5 2DS1 3DL2 Caucasian Caucasian Caucasian African American East Asian Asian Indian Caucasian East Asian Caucasian Caucasian Caucasian Caucasian East Asian East Asian • From ~1000 individuals: • 111 genotypes described

  7. Characterizng KIR Genotype Heterogeneity 100 100 100 100 50 50 50 50 Accumulated Frequency % Japanese n=105 10 Distribution patterns differ between populations African n=62 23 North Indian Hindu n=72 47 Caucasian Norman et al (2001): Immunogenetics 52 Norman et al (2002): Genes and Immunity 3 Rajalingam et al (2002): Immunogenetics 53 Uhrberg et al (2002): Immunogenetics 54 Yawata et al (2002): Immunogenetics 54 Toneva M et al (2001): Tissue Antigens 57 n=404 Total 51 Number of Genotypes

  8. Limited Number of KIR Genotypes in JapanesePredominance of the Group A Haplotypes (105 Japanese individuals)

  9. Caucasian 32% Palestinian North Indian Hindu 23% 6% Thai 35% Australian Aborigine <1% KIR Gene Content Differs Considerably between Population Groups Japanese 60% African 35% Norman et al (2001): Immunogenetics 52 Norman et al (2002): Genes and Immunty 3 Rajalingam et al (2002): Immunogenetics 53 Uhrberg et al (2002): Immunogenetics 54 Yawata et al (2002): Immunogenetics 54 Toneva M et al (2001): Tissue Antigens 57

  10. KIR Gene H A P L O T Y P E Allelic Polymorphism Distinguishes 22 Group A Haplotypes Having Identical Gene Content Shilling et al. 2002 J Immunol. 168:2307-15 Group A haplotype 2DS4 3DL3 2DL3 2DL1 2DL4 3DL1 3DL2 5 6 6 9 11 4 12 # alleles: > 800,000 possible combinations in the group A haplotypes

  11. KIR3DL1 Allotypes Show Distinct Cell Surface Phenotypes in DX9 Antibody Binding n=70

  12. NK Cell Repertoire:NK Cells Express Different Numbers and Combinations of KIR and CD94:NKG2 Receptors ISR ISR ISR ISR ISR ISR ISR ISR = Inhibitory Self Receptor

  13. KIR Repertoire Comparisons in Sibling Pairs Reveal the Effects of KIR-type 5 4 KIR-identical HLA-identical n=7 KIR-identical HLA-disparate n=19 3 2 1 0 5 4 KIR-disparate HLA-identical n=14 KIR-disparate HLA-disparate n=44 3 2 1 0 0 2 4 6 0 2 4 6 Summed differences in expression level Shilling et al. 2002 J Immunol. 169:239-47 Summed frequency differences KIR genotype is the primary determinant of KIR phenotype

  14. KIR Repertoire Comparisons in Sibling Pairs Reveal the Effects of HLA-type 2 1 0 0 1 2 3 Summed differences in expression level KIR-identical HLA-identical HLA-disparate Shilling et al. 2002 J Immunol. 169:239-47 Summed frequency differences HLA-type has a small influence on KIR phenotype

  15. KIR Incompatibility May Correlate with Better Clinical Outcome 1 Summed differences in MFI 1 1 N 1 1 2 2 1 2 1 1 2 1 N 1 1 2 1 N 2 1 1 N 1 N 1 2 Summed frequency differences NK Receptor Reconstitution Pattern Group 1 (good recovery) 1 Group 2 (delayed recovery) 2 Non-group 1 or 2 (clinical complications) N

  16. Gorilla Human Chimpanzee Bonobo Orangutan Rhesus Monkey Species-specific divergence of KIR lineages

  17. Recombination in the KIR gene family More than 40 % of the dataset was removed after the recombination analysis

  18. Ultimate phylogenetic tree of the KIR gene family

  19. Model for KIR lineage emergence in Primates

  20. KIR Diversity 1. Within a person, individual NK cells differ in the combination of KIR genes they express. This gives a repertoire of NK cell responsiveness. 2. Within a population, individual human beings have different combinations of KIR genes and KIR alleles. NK cell repertoires differ between individuals. 3. Within the human species, ethnic populations differ in the presence and frequency of KIR genes, alleles, haplotypes and genotypes. 4. Human KIR genes, alleles, haplotypes and genotypes markedly differ from those in other primate species. The KIR gene family evolves rapidly. Is KIR diversity the result of changing pressure from pathogens upon NK cell response? If so, what are the implications of KIR diversity for human health and the practice of medicine?

  21. NK cells are part of the innate immune response Early response to injury and infection

  22. 1.0 no KIR3DS1 or Bw4-80Ile only KIR3DS1 0.8 only Bw4-80Ile KIR3DS1 + Bw4-80Ile 0.6 0.4 RH p KIR3DS1 1.23 0.03 Bw4-80Ile 1.00 0.94 Both 0.58 0.0005 0.2 0 0 2 4 6 8 10 12 14 16 18 20 Epistatic Interaction Between KIR3DS1 and HLA-B Delays the Progression to AIDS Fraction of AIDS-free individuals Time since seroconversion (years) Martin et al 2002 Nat Genet 31:429-34

  23. Missing Self–MHC Class I Mechanism of Target Cell Lysis inhibition NK cell Resistant Healthy cell Inhibitory receptor HLA-I Activating receptor NK cell Susceptible Target cell lysis

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