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NK cells are part of the innate immune response. Early response to injury and infection. 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

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NK cells are part of the innate immune response

Early response to injury and infection


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

  • Allogeneic hematopoietic cell transplantation

    • mediate graft rejection

    • mediate graft vs leukemia (GVL)

    • prevent graft vs host disease (GVHD)

  • Control of infection

    • particularly virus infections


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


Ligand

Receptor

2DL1

HLA-Clys80

2DL2

HLA-Casn80

2DL3

HLA-Casn80

2DS1

HLA-Clys80

2DS2

2DS3

KIR

2DS4

2DS5

2DL4

HLA-G

2DL5

3DL1

HLA-B

3DL2

HLA-A

3DL3

3DS1

CD94

HLA-E

NKG2A

Lectin-like

receptors

CD94

HLA-E

NKG2C

NKG2E

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

Group B Haplotypes

3DL3

2DL3

2DL1

2DL4

3DS1

2DL5A

2DS5

2DS1

3DL2

1

2DS1

3DL2

3DL3

2DL3

2DL5B

2DS3

2DL1

2DL4

3DS1

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


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

Caucasian

East Asian

East Asian

  • From ~1000 individuals:

    • 111 genotypes described


Characterizng kir genotype heterogeneity
Characterizng KIR Genotype Heterogeneity

100

100

100

100

50

50

50

50

Accumulated Frequency

%

Japanese

n=105

10

Distribution patterns differ between populations

African

n=62

23

North Indian Hindu

n=72

47

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


Limited number of kir genotypes in japanese predominance of the group a haplotypes
Limited Number of KIR Genotypes in JapanesePredominance of the Group A Haplotypes

(105 Japanese individuals)


Caucasian

32%

Palestinian

North Indian Hindu

23%

6%

Thai

35%

Australian Aborigine

<1%

KIR Gene Content Differs Considerably between Population Groups

Japanese

60%

African

35%

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


KIR Gene

H

A

P

L

O

T

Y

P

E

Allelic Polymorphism Distinguishes 22 Group A Haplotypes Having Identical Gene Content

Shilling et al. 2002

J Immunol. 168:2307-15

Group A haplotype

2DS4

3DL3

2DL3

2DL1

2DL4

3DL1

3DL2

5

6

6

9

11

4

12

# alleles:

> 800,000 possible combinations in the group A haplotypes



NK Cell Repertoire: DX9 Antibody Binding 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

KIR-identical

HLA-identical

n=7

KIR-identical

HLA-disparate

n=19

3

2

1

0

5

4

KIR-disparate

HLA-identical

n=14

KIR-disparate

HLA-disparate

n=44

3

2

1

0

0

2

4

6

0

2

4

6

Summed

differences

in expression

level

Shilling et al. 2002

J Immunol. 169:239-47

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

1

0

0

1

2

3

Summed

differences

in expression

level

KIR-identical

HLA-identical

HLA-disparate

Shilling et al. 2002

J Immunol. 169:239-47

Summed frequency differences

HLA-type has a small influence on KIR phenotype


KIR Incompatibility May Correlate with Better Clinical Outcome

1

Summed

differences

in MFI

1

1

N

1

1

2

2

1

2

1

1

2

1

N

1

1

2

1

N

2

1

1

N

1

N

1

2

Summed frequency differences

NK Receptor Reconstitution Pattern

Group 1 (good recovery)

1

Group 2 (delayed recovery)

2

Non-group 1 or 2 (clinical complications)

N


Gorilla Outcome

Human

Chimpanzee

Bonobo

Orangutan

Rhesus Monkey

Species-specific divergence of KIR lineages


Recombination in the KIR gene family Outcome

More than 40 % of the dataset was removed after the recombination analysis




KIR Diversity Outcome

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 Outcome

Early response to injury and infection


1.0 Outcome

no KIR3DS1 or Bw4-80Ile

only KIR3DS1

0.8

only Bw4-80Ile

KIR3DS1 + Bw4-80Ile

0.6

0.4

RH p

KIR3DS1 1.23 0.03

Bw4-80Ile 1.00 0.94

Both 0.58 0.0005

0.2

0

0

2

4

6

8

10

12

14

16

18

20

Epistatic Interaction Between KIR3DS1 and HLA-B Delays the Progression to AIDS

Fraction

of AIDS-free

individuals

Time since seroconversion (years)

Martin et al 2002

Nat Genet 31:429-34


Missing Self–MHC Class I Mechanism of Target Cell Lysis Outcome

inhibition

NK

cell

Resistant

Healthy

cell

Inhibitory

receptor

HLA-I

Activating

receptor

NK

cell

Susceptible

Target

cell

lysis


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