NK cells are part of the innate immune response Early response to injury and infection
Functions: Natural Killer (NK) Cells. Cytolysis: killing infected or damaged cells 2. Cytokine production: IFNγ, GM-CSF, TNFα Control of the switch from innate to adaptive immunity interaction with dendritic cells Reproduction intrauterine NK cells establishment of the placenta tissue remodeling Control of infection particularly virus infections Allogeneic hematopoietic cell transplantation mediate graft rejection mediate graft vs leukemia (GVL) prevent graft vs host disease (GVHD)
Action of NK Cells is Mediated by a Balance of Inhibitory and Activating Receptors Inhibitory Receptors Tolerance to self KIR2DL KIR3DL LIR/ILT NKG2A LAIR NKP-R Activating Receptors Responsiveness to pathogens KIR2DS KIR3DS LIR/ILT NKG2C/E NKG2D NKR-P NKp30 NKp44 NKp46 NKp80 2B4
Ligand HLA-C lys80 HLA-C asn80 HLA-C asn80 HLA-C lys80 Receptor 2DL 2DL2 2DL3 2DS 2DS2 2DS3 2DS4 2DS5 KIR HLA-G HLA-B HLA-A 2DL4 2DL5 3DL 3DL2 3DL3 3DS HLA-E HLA-E CD94 NKG2A CD94 NKG2C NKG2E Lectin-like receptors Human KIR and CD94:NKG2A Receptors for HLA Class I
KIR Haplotype Diversity 9q3.4 Group A Haplotypes 3DL3 2DL3 2DL 2DL4 3DL 2DS4 3DL2 Group B Haplotypes 3DL3 2DL3 2DL 2DL4 3DS 2DL5A 2DS5 2DS 3DL2 2 3DL3 2DL3 2DL5B 2DS3 2DL 2DL4 3DS 2DS 3DL2 3 3DL3 2DS2 2DL2 2DL4 3DL 2DS4 3DL2 3DL3 2DS2 2DL2 2DL5B 2DS3 2DL 2DL4 3DS 2DL5A 2DS5 2DS 3DL2 4... Inhibitory KIR Activatory KIR
KIR Genotype Variation in a Panel of Individuals Donor ethnicity Caucasian Caucasian Caucasian African American East Asian Asian Indian Caucasian East Asian Caucasian Caucasian Caucasian Caucasian East Asian East Asian 3DL3 2DL3 2DS2 2DL2 2DL5 2DS3 2DL 2DL4 3DL 3DS 2DS4 2DS5 2DS 3DL2 From ~000 individuals: genotypes described
Accumulated Frequency % 00 50 00 50 n=05 0 Japanese African Characterizng KIR Genotype Heterogeneity Distribution patterns differ between populations n=62 23 00 50. North Indian Hindu n=72 47 00 50 n=404 Total 5 Number of Genotypes Caucasian Norman et al (200): 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 (200): Tissue Antigens 57
Limited Number of KIR Genotypes in Japanese Predominance of the Group A Haplotypes Genotype Assumed Haplotypes 2DL 3DL KIR genes 3DS 2DP 3DP # 2 3 4 5 2 3 2 3 4 5 A/A 60 2 A/B 7 3 A/B2 9 4 A/B3 6 5 A/B4 3 6 A/B5 2 7 A/B6 8 A/B7 9 A/B8 0 B/B 2DS % (05 Japanese individuals)
KIR Gene Content Differs Considerably between Population Groups Caucasian 32% Palestinian 23% North Indian Hindu Japanese 6% African Thai 60% 35% 35% Australian Aborigine <% Norman et al (200): 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 (200): Tissue Antigens 57
Group A haplotype Allelic Polymorphism Distinguishes 22 Group A Haplotypes Having Identical Gene Content H A P L O T Y P E 2 3 4 5 6 7 8 9 0 2 3 4 5 6 7 8 9 20 2 22 KIR Gene 3DL3 2DL3 2DL 2DL4 3DL 2DS4 3DL2 Shilling et al. 2002 J Immunol. 68:2307-5 3DL3 2DL3 2DL 2DL4 3DL 2DS4 3DL2 # alleles: 5 6 6 9 4 2 > 800,000 possible combinations in the group A haplotypes
KIR3DL Allotypes Show Distinct Cell Surface Phenotypes in DX9 Antibody Binding 350 300 250 MFI 200 50 00 3DL*00 3DL*005 3DL_007J 3DL_JA 3DL_JB 3DL_JA+JB 3DL_JA+00 50 0 0 0 20 30 40 50 Frequency n=70
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
KIR Repertoire Comparisons in Sibling Pairs Reveal the Effects of KIR-type 5 4 3 KIR-identical HLA-identical n=7 KIR-identical HLA-disparate n=9 2 Summed differences in expression level 0 5 4 3 KIR-disparate HLA-identical n=4 KIR-disparate HLA-disparate n=44 2 Shilling et al. 2002 J Immunol. 69:239-47 0 0 2 4 6 0 2 4 6 Summed frequency differences KIR genotype is the primary determinant of KIR phenotype
KIR Repertoire Comparisons in Sibling Pairs Reveal the Effects of HLA-type 2 Summed differences in expression level KIR-identical HLA-identical HLA-disparate 0 0 2 3 Summed frequency differences Shilling et al. 2002 J Immunol. 69:239-47 HLA-type has a small influence on KIR phenotype
KIR Incompatibility May Correlate with Better Clinical Outcome 6 5 Summed differences in MFI 4 3 2 2 2 N 2 2 2 2 N 2 N N N 0 0 2 3 4 5 6 Summed frequency differences NK Receptor Reconstitution Pattern 2 Group (good recovery) Group 2 (delayed recovery) N Non-group or 2 (clinical complications)
D0 Gorilla Human Chimpanzee Bonobo Orangutan Rhesus Monkey D D2 STM CYT D0 D D2 STM CYT D0 D D2 STM CYT D0 D D2 STM CYT D0 D D2 STM CYT D0 D D2 STM CYT I II III IV V Species-specific divergence of KIR lineages
Recombination in the KIR gene family More than 40 % of the dataset was removed after the recombination analysis
Mouse Bota-KIR2DL 83 85:b 55 Pt-KIR3DL/2 KIR3DL KIR3DS KIR3DL/2V KIR3DL2 Gg-KIR3DLa Popy-KIR3DS Popy-KIR3DLA Pt-KIR3DL5 Gg-KIR3DL7 Pt-KIR3DS2 Pt-KIR3DL4 Pp-KIR3DL4 KIR2DS5 KIR2DS KIR2DL KIR2DS2 KIR2DL3 KIR2DL2 Gg-KIR2DLe Pt-KIR2DL6 Gg-KIR2DL6 Gg-KIR2DLd KIR2DS4 Pt-KIR2DS4 Popy-KIR2DSC2 Popy-KIR2DLB Popy-KIR2DSD Popy-KIR2DLA KIR2DL5 Pt-KIR2DL5 Gg-KIR2DL5 00 83 89 00 00 99 87 00 93 97 56 89 00 99 98 84 00 7:b 6 99:b 78 74:b 6 98:b 70 99:a 88 99:a 80 98:a 64 84:a 67 74:b * 82:b * 69:b * 95 99 Mm-KIR2DL4. Popy-KIR2DL4B KIR2DL4 Gg-KIR2DL4 Pt-KIR2DL4 Pp-KIR2DL4 84 83 95 57:b * 95:a 6 Mm-KIRD Mm-KIR3DH Mm-KIR3DH2 Mm-KIR3DL8 Mm-KIR3DH3 Mm-KIR3DL9 Mm-KIR3DL0 Mm-KIR3DH4 Mm-KIR3DL8 Mm-KIR3DL7 Mm-KIR3DL5 Mm-KIR3DL Mm-KIR3DL3 Mm-KIR3DL4 96:b 72 00 83 79 83 00 * 00 00 00 88:a 60 97:b 53 87 I-A I-B II III IV // // // // Ultimate phylogenetic tree of the KIR gene family
Model for KIR lineage emergence in Primates
KIR Diversity. 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?
NK cells are part of the innate immune response Early response to injury and infection
Epistatic Interaction Between KIR3DS and HLA-B Delays the Progression to AIDS.0 no KIR3DS or Bw4-80Ile only KIR3DS Fraction of AIDS-free individuals 0.8 0.6 0.4 only Bw4-80Ile KIR3DS + Bw4-80Ile 0.2 0 RH p KIR3DS.23 0.03 Bw4-80Ile.00 0.94 Both 0.58 0.0005 0 2 4 6 8 0 2 4 6 8 20 Time since seroconversion (years) Martin et al 2002 Nat Genet 3:429-34
Missing Self MHC Class I Mechanism of Target Cell Lysis inhibition NK cell Inhibitory receptor Activating receptor HLA-I Resistant Healthy cell NK cell Susceptible Target cell lysis