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NK cells are part of the innate immune response
Early response to injury and infection NK cells are part of the innate or natural immune response, where they act as a first line of defence against injury and infection. They act early during the immune response, typically during the first week of an infection, to decrease viral loads to a level that is then manageable for the adaptive T cell response. The importance of NK cell immunity is highlighted by the fact that individuals who lack functional NK cells are rare, and that such NK-deficient people are typically plagued by severe, recurrent viral infections.
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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 NK cells have 2 primary roles in the body. The first is the direct killing of cells that have lost or altered MHC class I expression. The second is the production of cytokines, such as IFN-g which then act on other cells of the adaptive immune response. NK cells play an important role in viral immunity, and in transplantation, where they have been show to mediate GVL effects, and to prevent GVHD by killing host APC. Allogeneic hematopoietic cell transplantation mediate graft rejection mediate graft vs leukemia (GVL) prevent graft vs host disease (GVHD) Control of infection particularly virus infections
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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 So the action of NK cells is mediated by a balance between inhibitory and activating receptors on the cell surface. While inhibitory receptors appear to be primarily involved in the killing of cells that have a different MHC class I specificity, and hence in maintaining self-tolerance, the role of the activating receptors is less well defined. Recent work, however has suggested that activating receptors are involved in the NK cell response to pathogens.
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Human KIR and CD94:NKG2A Receptors for HLA Class I
Ligand Receptor HLA-Clys80 2DL1 HLA-Casn80 2DL2 HLA-Casn80 2DL3 HLA-Clys80 2DS1 2DS2 2DS3 KIR 2DS4 2DS5 HLA-G 2DL4 2DL5 HLA-B 3DL1 HLA-A 3DL2 3DL3 In humans, inhibitory and activating receptors on NK cells are encoded by 2 different multigene families, the KIR which stands for killer-Ig-like receptor, and the lectin-like CD94:NKG2 heterodimers. I should mention that there are several other families of genes that encode NK cell receptors, however our lab has focused on the KIR and lectin-based receptors because they are MHC class I-specific and are the most variable. 14 different KIR genes encode receptors on NK cells, and some recognize HLA class I determinants. KIR are classified based on the number of Ig domains they contain (2D or 3D) and on the length of their cytoplasmic tail. Long-tailed KIR (or L KIR) contain immuno-receptor based inhibitory motifs (or ITIMs) and encode inhibitory receptors, while short-tailed KIR (or S KIR) have short cytoplasmic tail, lack ITIMs and are activating. The lectin-like CD94:NKG2 receptors are structurally distinct from the KIR, although they also have both inhibitory and activating isoforms, and they interact with the non-classical MHC class I molecule HLA-E. 3DS1 CD94 HLA-E NKG2A Lectin-like receptors CD94 HLA-E NKG2C NKG2E Human KIR and CD94:NKG2A Receptors for HLA Class I
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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 3DL3 2DL3 2DL5B 2DS3 2DL1 2DL4 3DS1 2DS1 3DL2 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
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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 I have shown here representative genotypes from a small group of individuals of mixed ethnicity (they happen to be the members of the Parham laboratory). As you can see, several individuals are homozygous for the A haplotypes, that is the one with the simplest combination of genes, while several individuals have B haplotypes of variable gene content. Similar to the MHC, there are ethnic differences in KIR genotype, such that some genotypes are more prevalent in certain populations. For example, genotypes homozygous for the A haplotypes tend to be more prevalent in the Japanese, while genotypes containing B haplotypes are more common in other ethnic groups, such as the Australian Aborigines. So far about 1000 ethnically diverse individuals have been examined, and 111 different KIR genotypes and 23 haplotypes have been defined. Caucasian East Asian East Asian From ~1000 individuals: 111 genotypes described
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Characterizng KIR Genotype Heterogeneity
Accumulated Frequency Characterizng KIR Genotype Heterogeneity % 100 50 Japanese n=105 10 Distribution patterns differ between populations 100 50 African n=62 23 100 50 North Indian Hindu n=72 47 100 50 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
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Limited Number of KIR Genotypes in Japanese Predominance of the Group A Haplotypes
(105 Japanese individuals)
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KIR Gene Content Differs Considerably between Population Groups
Caucasian 32% Palestinian 23% North Indian Hindu 6% Japanese 60% Thai 35% African 35% Australian Aborigine <1% 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
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Allelic Polymorphism Distinguishes 22 Group A Haplotypes Having Identical Gene Content
KIR Gene H A P L O T Y E Shilling et al. 2002 J Immunol. 168: Group A haplotype 3DL3 2DL3 2DL1 2DL4 3DL1 2DS4 3DL2 # alleles: 5 6 6 9 11 4 12 > 800,000 possible combinations in the group A haplotypes
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KIR3DL1 Allotypes Show Distinct Cell Surface Phenotypes in DX9 Antibody Binding
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NK Cell Repertoire: NK Cells Express Different Numbers and Combinations of KIR and CD94:NKG2 Receptors ISR ISR ISR ISR ISR Unlike T and B cells, diversity in the NK cell compartment within an individual is not achieved by gene rearrangement. Instead, each NK cell expresses a different number and combination of KIR and CD94:NKG2 receptors such that a repertoire of expression is formed. We can then use monoclonal antibodies directed against these surface molecules to measure the relative proportion of cells that express a certain receptor. In this manner, we can assess the KIR repertoire of an individual. The expression of any particular receptor on the cell surface is stochastic or random, the only caveat being that every NK cell must express at least 1 inhibitory receptor capable of recognizing self-MHC in order to maintain self tolerance. ISR ISR ISR = Inhibitory Self Receptor
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KIR Repertoire Comparisons in Sibling Pairs Reveal the Effects of KIR-type
KIR-identical HLA-identical n=7 HLA-disparate n=19 KIR-disparate n=44 n=14 2 4 6 1 3 5 Summed differences in expression level To assess the impact of KIR and HLA genotype on KIR repertoire, Heather Shilling, a former graduate student in the Parham lab, examined KIR repertoire in 85 sibling pairs using the method I just described on the previous 2 slides. She divided each sibling pair into those that were KIR-identical and HLA-identical, KIR-identical and HLA-different, KIR-different and HLA-identical, and KIR-different and HLA-different. She found that sibling pairs who were KIR-identical had more similar KIR repertoires, as evidenced by the data points being closer to the origin, as compared to the KIR-disparate sibling pairs. This similarity was seen regardless of whether the sibling pairs were HLA-identical or not. Therefore, KIR genotype appears to be the primary determinant of KIR phenotype. Shilling et al. 2002 J Immunol. 169:239-47 Summed frequency differences KIR genotype is the primary determinant of KIR phenotype
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KIR Repertoire Comparisons in Sibling Pairs Reveal the Effects of HLA-type
1 2 3 Summed differences in expression level KIR-identical HLA-identical HLA-disparate But, does HLA also have an effect? This plot combines the top 2 panels from the last slide, but please notice that the scale in this graph is much more condensed. As you can see, the KIR repertoires of the KIR-identical and HLA-identical sibling pairs, shown in orange, are located much closer to the origin than the HLA-different pairs. This indicates that while KIR genotype itself is the primary determinant of KIR phenotype, HLA has a slight, modifying influence. Shilling et al. 2002 J Immunol. 169:239-47 Summed frequency differences HLA-type has a small influence on KIR phenotype
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KIR Incompatibility May Correlate with Better Clinical Outcome
1 Summed differences in MFI 1 1 N 1 1 2 2 2 1 1 2 1 N 1 1 1 2 2 N 1 N 1 1 N 1 1 2 Summed frequency differences NK Receptor Reconstitution Pattern 1 Group 1 (good recovery) 2 Group 2 (delayed recovery) N Non-group 1 or 2 (clinical complications)
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Species-specific divergence of KIR lineages
Gorilla Human Chimpanzee Bonobo Orangutan Rhesus Monkey Species-specific divergence of KIR lineages
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Recombination in the KIR gene family
More than 40 % of the dataset was removed after the recombination analysis
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Ultimate phylogenetic tree of the KIR gene family
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Model for KIR lineage emergence in Primates
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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?
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NK cells are part of the innate immune response
Early response to injury and infection NK cells are part of the innate or natural immune response, where they act as a first line of defence against injury and infection. They act early during the immune response, typically during the first week of an infection, to decrease viral loads to a level that is then manageable for the adaptive T cell response. The importance of NK cell immunity is highlighted by the fact that individuals who lack functional NK cells are rare, and that such NK-deficient people are typically plagued by severe, recurrent viral infections.
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Epistatic Interaction Between KIR3DS1 and HLA-B Delays the Progression to AIDS
0.2 0.4 0.6 0.8 1.0 2 4 6 8 10 12 14 16 18 20 no KIR3DS1 or Bw4-80Ile only KIR3DS1 only Bw4-80Ile KIR3DS1 + Bw4-80Ile RH p KIR3DS Bw4-80Ile Both Fraction of AIDS-free individuals Time since seroconversion (years) Martin et al 2002 Nat Genet 31:429-34
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Missing Self–MHC Class I Mechanism of Target Cell Lysis
inhibition NK cell Inhibitory receptor Resistant Healthy cell HLA-I Activating receptor NK cell Susceptible Target cell As I mentioned in the previous slide, NK cells kill target cells that have altered or lost MHC class I expression. This ability of NK cells to recognize missing self was first described by Klas Karre in the mid-1980’s and has subsequently been shown to be mediated by the balance of activating and inhibitory receptors on the cell surface. When an NK cell encounters a normal, healthy target cell, inhibitory receptors on the surface interact with their specific self-MHC class I ligands. This interactions sends an inhibitory signal to the NK cell, which turns it off and prevents it from killing the normal healthy target. When the NK cell encounters a target cell that has altered its MHC class I expression in some way, inhibitory receptors do not interact with their ligands, and the NK cell is then able to lyse the target, presumably by interaction through an activating receptor. lysis
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