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NK cells are part of the innate immune response
Early response to injury and infection
Natural Killer (NK) Cells
Functions:
1. Cytolysis: killing infected or damaged cells
2. Cytokine production: IFN, GM-CSF, TNF
Control of the switch from
innate to adaptive immunity
• interaction with dendritic cells
Control of infection
• particularly virus infections
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)
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-R1
Activating
Receptors
Responsiveness
to pathogens
KIR2DS
KIR3DS
LIR/ILT
NKG2C/E
NKG2D
NKR-P1
NKp30
NKp44
NKp46
NKp80
2B4
Ligand
Receptor
HLA-Clys80
2DL1
HLA-Casn80
2DL2
HLA-Casn80
2DL3
HLA-Clys80
2DS1
2DS2
2DS3
2DS4
KIR
2DS5
HLA-G
2DL4
HLA-B
2DL5
3DL1
HLA-A
3DL2
3DL3
3DS1
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
19q13.4
Group A Haplotypes
3DL3 2DL3
2DL1
2DL4
3DL1
2DS4 3DL2
2DL1
2DL4
3DS1 2DL5A 2DS5 2DS1
3DL2
2DL1
2DL4
3DS1
2DS1
3DL2
2DL4
3DL1
Group B Haplotypes
3DL3 2DL3
1
3DL3 2DL3
2DL5B 2DS3
2
3DL3 2DS2 2DL2
2DS4 3DL2
3
3DL3 2DS2 2DL2
2DL5B
2DS3
2DL1
2DL4
3DS1 2DL5A 2DS5 2DS1
3DL2
4
.
.
.
Inhibitory KIR
Activatory KIR
KIR Genotype Variation in a Panel of Individuals
Donor ethnicity
Caucasian
Caucasian
Caucasian
3DL3 2DL3 2DS2 2DL2 2DL5 2DS3 2DL1 2DL4 3DL1 3DS1 2DS4 2DS5 2DS1 3DL2
African American
East Asian
Asian Indian
Caucasian
East Asian
Caucasian
Caucasian
Caucasian
Caucasian
East Asian
East Asian
From ~1000 individuals:
• 111 genotypes described
Accumulated Frequency
%
100
Japanese
50
n=105
Characterizng KIR
Genotype Heterogeneity
10
Distribution patterns differ
between populations
100
50
African
n=62
23
100
50
North Indian Hindu
.
n=72
47
100
Caucasian
50
n=404
Total 51
Number of Genotypes
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
Limited Number of KIR Genotypes in Japanese
Predominance of the Group A Haplotypes
Genotype
Assumed
KIR genes
2DL
Haplotypes
#
1
1
A/A
2
A/B1
3
A/B2
4
A/B3
5
A/B4
6
A/B5
7
A/B6
8
A/B7
9
A/B8
10
B/B
2
3
3DL
4
5
1
2
2DS
3
1
2
3
3DS 2DP 3DP
4
5
1
1
%
1
60
17
9
6
3
2
1
1
1
1
(105 Japanese individuals)
KIR Gene Content Differs Considerably between
Population Groups
Caucasian
32%
Palestinian
23%North Indian Hindu
Japanese
6%
60%
Thai
African
35%
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
Allelic Polymorphism Distinguishes 22 Group A
Haplotypes Having Identical Gene Content
KIR Gene
3DL3 2DL3 2DL1 2DL4 3DL1 2DS4 3DL2
H
A
P
L
O
T
Y
P
E
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Shilling et al. 2002
J Immunol. 168:2307-15
Group A haplotype
# alleles:
3DL3
2DL3
5
6
2DL1
6
> 800,000 possible combinations in the group A haplotypes
2DL4
3DL1
2DS4
3DL2
9
11
4
12
KIR3DL1 Allotypes Show Distinct Cell Surface
Phenotypes in DX9 Antibody Binding
350
300
250
3DL1*001
MFI
200
3DL1*005
3DL1_007J
150
3DL1_JA
3DL1_JB
3DL1_JA+JB
100
3DL1_JA+001
50
0
0
10
20
30
Frequency
40
50
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 = Inhibitory Self Receptor
ISR
KIR Repertoire Comparisons in Sibling Pairs Reveal the
Effects of KIR-type
5
KIR-identical
4 HLA-identical
n=7
3
KIR-identical
HLA-disparate
n=19
2
1
Summed
differences
in expression
level
0
5
KIR-disparate
4 HLA-identical
n=14
3
KIR-disparate
HLA-disparate
n=44
Shilling et al. 2002
J Immunol. 169:239-47
2
1
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 1
level
KIR-identical
HLA-identical
HLA-disparate
0
0
1
2
3
Summed frequency differences
HLA-type has a small influence on KIR phenotype
Shilling et al. 2002
J Immunol. 169:239-47
KIR Incompatibility May Correlate with Better Clinical Outcome
6
5
4
Summed
differences
in MFI
1
1
3
1N
1
2
2
1
2
2
N
2
1
21 2 1
1
1
N12
1
1 1
N
N 1 1
1
0
0
1
2
3
4
5
6
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)
Gorilla
Gorilla
D0
D1
D2 STM CYT
Human
Human
D0
D1
D2 STM CYT
Chimpanzee
Chimpanzee
D0
D1
D2 STM CYT
Bonobo
Bonobo
D0
D1
D2 STM CYT
Orangutan
Orangutan
D0
D1
D2 STM CYT
Rhesus
Rhesus Monkey
Monkey
D0
D1
I
II
III
IV
V
Species-specific divergence of KIR lineages
D2 STM CYT
Recombination in the KIR gene family
More than 40 % of the dataset was removed after the recombination analysis
Ultimate phylogenetic tree of the KIR gene family
//
//
Mouse
Bota-KIR2DL1
Pt-KIR3DL1/2
100:a
KIR3DL1
89
100:a
KIR3DS1
100
74:b
69:b
KIR3DL1/2V
*
*
KIR3DL2
82:b
100:a
*
Gg-KIR3DLa
83
Popy-KIR3DS
100:a
100
Popy-KIR3DLA
Pt-KIR3DL5
100:a
99
Gg-KIR3DL7
98:a
Pt-KIR3DS2
64
100:a
Pt-KIR3DL4
100 100:a
95
100:a
Pp-KIR3DL4
93
KIR2DS5
100:a
KIR2DS1
84:a
100:a
87
67
97
KIR2DL1
KIR2DS2
100:a
KIR2DL3
100
99:a
KIR2DL2
80
100:a
Gg-KIR2DLe
56 100:a
100:a
84 99:a
Pt-KIR2DL6
89
88
Gg-KIR2DL6
Gg-KIR2DLd
98:b
KIR2DS4
100:a
70
100
Pt-KIR2DS4
Popy-KIR2DSC2
100:a
98
Popy-KIR2DLB
100:a
99
Popy-KIR2DSD
100:a
99
Popy-KIR2DLA
KIR2DL5
100:a
Pt-KIR2DL5
100
74:b
Gg-KIR2DL5
99:b
78
//
71:b
61
//
100:a
83
61
100:a
84
100:a
83
100:a
95
57:b
*
95:a
61
85:b
55
96:b
72
Mm-KIR2DL4.1
Popy-KIR2DL4B
KIR2DL4
Gg-KIR2DL4
Pt-KIR2DL4
Pp-KIR2DL4
Mm-KIR1D
97:b
Mm-KIR3DH1
53
Mm-KIR3DH2
100:a
Mm-KIR3DL18
79
100:a
Mm-KIR3DH3
100:a
83
Mm-KIR3DL9
83
100:a
100
Mm-KIR3DL10
100:a
Mm-KIR3DH4
100:a
* 100:a
100
Mm-KIR3DL8
87
100:a
100
Mm-KIR3DL17
Mm-KIR3DL5
100:a
Mm-KIR3DL1
100
Mm-KIR3DL3
88:a 100:a
60 100
Mm-KIR3DL4
II
III
I-A
I-B
IV
Model for KIR lineage emergence in Primates
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?
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
1.0
no KIR3DS1 or Bw4-80Ile
only KIR3DS1
0.8
only Bw4-80Ile
KIR3DS1 + Bw4-80Ile
Fraction
of AIDS-free
individuals
0.6
0.4
0.2
RH p
1.23 0.03
1.00 0.94
0.58 0.0005
KIR3DS1
Bw4-80Ile
Both
0
0
2
4
6
8
10
12
14
16
18
20
Time since seroconversion (years)
Martin et al 2002
Nat Genet 31:429-34
Missing Self–MHC Class I Mechanism of Target Cell Lysis
inhibition
Inhibitory
receptor HLA-I
Resistant
Healthy
cell
NK
cell
Activating
receptor
Susceptible
Target
cell
NK
cell
lysis