early response to injury and infection
TRANSCRIPT
NK cells are part of the innate immune response
Early response to injury and infection
Natural Killer (NK) Cells
Allogeneic hematopoietic cell transplantation• mediate graft rejection• mediate graft vs leukemia (GVL)• prevent graft vs host disease (GVHD)
Control of infection• particularly virus infections
1. Cytolysis: killing infected or damaged cells2. Cytokine production: IFNγγγγ, GM-CSF, TNFαααα
Functions:
Reproduction• intrauterine NK cells• establishment of the placenta• tissue remodeling
Control of the switch frominnate to adaptive immunity
• interaction with dendritic cells
Inhibitory Receptors
ActivatingReceptors
Toleranceto self
Responsivenessto pathogens
Action of NK Cells is Mediated by a Balance of Inhibitory and Activating Receptors
KIR2DLKIR3DLLIR/ILTNKG2A
LAIRNKP-R1
KIR2DSKIR3DSLIR/ILT
NKG2C/ENKG2DNKR-P1NKp30NKp44NKp46NKp80
2B4
KIR
HLA-Clys80
Lectin-like receptors
CD94NKG2A
CD94NKG2CNKG2E
Ligand2DL1
2DL2
2DL3
2DS1
2DS2
2DS3
2DS4
2DS5
HLA-E
3DL1
3DL2
3DS13DL3
HLA-B
HLA-A
HLA-E
2DL4
2DL5HLA-G
Receptor
HLA-Casn80
HLA-Casn80
HLA-Clys80
Human KIR and CD94:NKG2A Receptors for HLA Class I
KIR Haplotype Diversity
3DL3 2DL3 2DL1 2DL4 3DL1 2DS4 3DL2
3DL3 2DL1 2DL4 3DS12DL3 2DL5B 2DS3 2DS1
2
2DL23DL3 2DS2 2DL4 3DL1 3DL22DS4
3
3DL3 2DS2 2DL1 2DL4 3DS1 2DS1 3DL22DL2 2DL5A 2DS52DL5B 2DS3
4
3DL3 2DL3 2DL1 2DL4 3DS1 3DL2
12DS12DL5A 2DS5
3DL2
Group A Haplotypes
Group B Haplotypes
19q13.4
.
.
.Inhibitory KIR
Activatory KIR
KIR Genotype Variation in a Panel of Individuals
From ~1000 individuals:• 111 genotypes described
3DL3 2DL3 2DS2 2DL2 2DL5 2DS3 2DL1 2DL4 3DL1 3DS1 2DS4 2DS5 2DS1 3DL2CaucasianCaucasianCaucasianAfrican AmericanEast Asian
Asian Indian
CaucasianEast AsianCaucasian
CaucasianCaucasianCaucasian
East Asian
East Asian
Donor ethnicity
Caucasian
African
JapaneseCharacterizng KIR
Genotype Heterogeneity
North Indian Hindu.
47
23
Total 51
n=62
n=72
n=404
Number of Genotypes
10
100
50
n=105
%
100
50
100
50
100
50
Accumulated Frequency
Norman et al (2001): Immunogenetics 52Norman et al (2002): Genes and Immunity 3Rajalingam et al (2002): Immunogenetics 53Uhrberg et al (2002): Immunogenetics 54Yawata et al (2002): Immunogenetics 54Toneva M et al (2001): Tissue Antigens 57
Distribution patterns differ between populations
Assumed
Haplotypes 3DS 2DP 3DP# 1 2 3 4 5 1 2 3 1 2 3 4 5 1 1 11 A/A 602 A/B1 173 A/B2 94 A/B3 65 A/B4 36 A/B5 27 A/B6 18 A/B7 19 A/B8 1
10 B/B 1
%3DL Genotype
2DL 2DS
KIR genes
Limited Number of KIR Genotypes in Japanese
Predominance of the Group A Haplotypes
(105 Japanese individuals)
African
Japanese
KIR Gene Content Differs Considerably between Population Groups
Norman et al (2001): Immunogenetics 52Norman et al (2002): Genes and Immunty 3Rajalingam et al (2002): Immunogenetics 53Uhrberg et al (2002): Immunogenetics 54Yawata et al (2002): Immunogenetics 54Toneva M et al (2001): Tissue Antigens 57
60%Thai
35%35%
Palestinian
23%
Caucasian
32%
Australian Aborigine
<1%
North Indian Hindu
6%
Allelic Polymorphism Distinguishes 22 Group A Haplotypes Having Identical Gene Content
3DL3 2DL3 2DL1 2DL4 3DL1 2DS4 3DL2123456789
10111213141516171819202122
KIR Gene
HAPLOTYPE
Group A haplotype2DL1 2DS4 3DL23DL12DL42DL33DL3
# alleles: 11 4 129665
> 800,000 possible combinations in the group A haplotypes
Shilling et al. 2002J Immunol. 168:2307-15
KIR3DL1 Allotypes Show Distinct Cell Surface Phenotypes in DX9 Antibody Binding
0
50
100
150
200
250
300
350
0 10 20 30 40 50
Frequency
MF
I
3DL1*001
3DL1*005
3DL1_007J
3DL1_JA
3DL1_JB
3DL1_JA+JB
3DL1_JA+001
n=70
NK Cell Repertoire:NK Cells Express Different Numbers and Combinations of KIR
and CD94:NKG2 Receptors
ISR = Inhibitory Self Receptor
ISR
ISR
ISR ISR
ISR
ISR
ISR
Summed frequency differences
Summed differences
in expressionlevel
KIR-identicalHLA-identicaln=7
KIR-identicalHLA-disparaten=19
KIR-disparateHLA-disparaten=44
KIR-disparateHLA-identicaln=14
0 2 4 6 0 2 4 60
1
2
3
4
50
1
2
3
4
5
Shilling et al. 2002J Immunol. 169:239-47
KIR Repertoire Comparisons in Sibling Pairs Reveal the Effects of KIR-type
KIR genotype is the primary determinant of KIR phenotype
1 2 300
2
1
Summed frequency differences
Summed differences
in expressionlevel
HLA-identicalHLA-disparate
KIR-identical
Shilling et al. 2002J Immunol. 169:239-47
KIR Repertoire Comparisons in Sibling Pairs Reveal the Effects of HLA-type
HLA-type has a small influence on KIR phenotype
1
2
0
1
2
3
4
5
6
0 1 2 3 4 5 6
KIR Incompatibility May Correlate with Better Clinical Outcome
Group 1 (good recovery)
Group 2 (delayed recovery)
Non-group 1 or 2 (clinical complications)
NK Receptor Reconstitution PatternSummed frequency differences
Summeddifferences
in MFI
2N
2
2
22
N N
2 2
N
N
11
1
1
1
111
1 1
1111
1
1
N
Species-specific divergence of KIR lineages
Bonobo
III
ChimpanzeeHuman Orangutan Rhesus MonkeyGorilla
I
II
D0 D2D1 STM CYT
IV
V
D0 D2D1 STM CYT D0 D2D1 STM CYT D0 D2D1 STM CYT D0 D2D1 STM CYT D0 D2D1 STM CYT
Gorilla Human Chimpanzee Bonobo Orangutan Rhesus Monkey
Recombination in the KIR gene family
More than 40 % of the dataset was removed after the recombination analysis
MouseBota-KIR2DL1
100:a83
85:b55
Pt-KIR3DL1/2KIR3DL1
KIR3DS1KIR3DL1/2V
KIR3DL2Gg-KIR3DLa
Popy-KIR3DSPopy-KIR3DLAPt-KIR3DL5Gg-KIR3DL7
Pt-KIR3DS2Pt-KIR3DL4
Pp-KIR3DL4KIR2DS5KIR2DS1
KIR2DL1KIR2DS2
KIR2DL3KIR2DL2
Gg-KIR2DLePt-KIR2DL6
Gg-KIR2DL6Gg-KIR2DLd
KIR2DS4Pt-KIR2DS4
Popy-KIR2DSC2Popy-KIR2DLB
Popy-KIR2DSDPopy-KIR2DLA
KIR2DL5Pt-KIR2DL5
Gg-KIR2DL5
100:a100
100:a83
100:a89 100:a
100
100:a100
100:a99
100:a87
100:a100
100:a93
100:a97
100:a56
100:a89
100:a100
100:a99
100:a98
100:a84
100:a100
71:b61
99:b78
74:b61
98:b70
99:a88
99:a80
98:a64
84:a67
74:b*
82:b*
69:b*
100:a95
100:a99
Mm-KIR2DL4.1Popy-KIR2DL4B
KIR2DL4Gg-KIR2DL4
Pt-KIR2DL4Pp-KIR2DL4
100:a84 100:a
83 100:a95 57:b
*
95:a61
Mm-KIR1DMm-KIR3DH1
Mm-KIR3DH2Mm-KIR3DL18Mm-KIR3DH3
Mm-KIR3DL9Mm-KIR3DL10
Mm-KIR3DH4Mm-KIR3DL8Mm-KIR3DL17
Mm-KIR3DL5Mm-KIR3DL1
Mm-KIR3DL3Mm-KIR3DL4
96:b72
100:a100
100:a83
100:a79
100:a83 100:a
100100:a
*100:a100
100:a100
100:a100
88:a60
97:b53
100:a87
I-A
I-B
II
III
IV
//
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Ultimate phylogenetic tree of the KIR gene family
Model for KIR lineage emergence in Primates
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.
KIR Diversity
Is KIR diversity the result of changing pressure from pathogens upon NKcell response?
If so, what are the implications of KIR diversity for human health and thepractice of medicine?
NK cells are part of the innate immune response
Early response to injury and infection
Epistatic Interaction Between KIR3DS1 and HLA-B Delays the Progression to AIDS
0
0.2
0.4
0.6
0.8
1.0
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 pKIR3DS1 1.23 0.03Bw4-80Ile 1.00 0.94Both 0.58 0.0005
Time since seroconversion (years)
Fractionof AIDS-freeindividuals
Martin et al 2002Nat Genet 31:429-34
Missing Self–MHC Class I Mechanism of Target Cell Lysis
NKcell
ResistantHealthy
cell
SusceptibleTarget
cell
HLA-I
inhibition
lysis
NKcell
Inhibitoryreceptor
Activatingreceptor