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

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: IFN, GM-CSF, TNF

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

3DS1

3DL3

HLA-B

HLA-A

HLA-E

2DL4

2DL5

HLA-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

1

2DS12DL5A 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 3DL2Caucasian

Caucasian

Caucasian

African American

East Asian

Asian Indian

Caucasian

East Asian

Caucasian

Caucasian

Caucasian

Caucasian

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 1

1 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 110 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

3DL32DL32DL12DL43DL12DS43DL2123456789

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

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


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 differences

in expressionlevel

HLA-identical

HLA-disparate

KIR-identical


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 Pattern


Summeddifferences

in MFI

2N

2

2

22

NN

2 2

N

N

11

1

1

1

111

1 1

1111

1

1

N

Species-specific divergence of KIR lineages

BonoboIIIChimpanzeeHumanOrangutanRhesusMonkeyGorillaIIID0D2D1STMCYTIVVD0D2D1STMCYTD0D2D1STMCYTD0D2D1STMCYTD0D2D1STMCYTD0D2D1STMCYTGorilla 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-KIR3DLA

Pt-KIR3DL5Gg-KIR3DL7

Pt-KIR3DS2Pt-KIR3DL4

Pp-KIR3DL4KIR2DS5KIR2DS1

KIR2DL1KIR2DS2

KIR2DL3KIR2DL2

Gg-KIR2DLe

Pt-KIR2DL6Gg-KIR2DL6

Gg-KIR2DLdKIR2DS4

Pt-KIR2DS4Popy-KIR2DSC2

Popy-KIR2DLBPopy-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



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

//

//

//

//

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

Documents

NK cells are part of the innate immune response