1

Evolution of the Interactions between MHC class I and Killer Immunoglobulin-like

Receptors (KIR)

Peter Parham Department of Structural Biology Stanford University School of Medicine California, USA

Functions of Natural Killer (NK) cells

Immune system Innate immunity. Kill virus-infected and cancerous cells. Adaptive immunity Activate myeloid cells.

Reproductive system Embryo implantation. Maternal uterine NK cells co-operate with fetal trophoblast cells in enlarging maternal arteries supplying blood to the placenta.

Evolution of the Interactions between MHC class I and Killer Immunoglobulin-like Receptors (KIR)

1.  Co-evolution of polymorphic MHC class I and variable NK cell receptors creates the species-specificity of NK-cell biology.

2.  The uniquely human NK-cell compromise between battling bugs and building bigger-brained babies.

Evolution of the Interactions between MHC class I and Killer Immunoglobulin-like Receptors (KIR)

1.  Co-evolution of polymorphic MHC class I and variable NK cell receptors creates the species-specificity of NK-cell biology.

2.  The uniquely human NK-cell compromise between battling bugs and building bigger-brained babies.

3.  The quality of the modern human NK-cell response in non-African populations was improved by contributions from their older, more experienced Archaic relatives.

2

Three Genetic Complexes Control the Development and Function of NK cells

KIR and T-cell Receptors Bind Overlapping Sites on HLA class I, Sensing Bound Peptide

KIR Recognize and Distinguish Four Epitopes of HLA-A,-B,and -C

The KIR Family Evolved ‘Recently’ in Simian Primates and Exhibits Considerable Species-specific Character

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Co-evolution of Primate KIR with the MHC Class I Epitopes they Recognize

Parham et al 2010 J Med Primatol.

2DL4 3DL1/2

2DL7 2DL8 3DL5 3DL4 2DL9 3DS2

3DL3

2DL5 2DL6 3DS6

FCAR

2DS4

LILR

2DS1 2DS3/5 2DL5A 3DS1

2DL4 3DL2 FCAR

2DL5B 2DL2 2DS2 2DS3/5

2DL3 3DL1

3DL3 3DP1 2DL1 2DP1 LILR

2DS4

C1 C1

C1 C2 C2

C2

C2 C2 C2

C2 C2

E44 C2

C1 C1

Chimpanzee

Human

C1

C1

Strong Variable Selection Drives Species-Specific Evolution of KIR as Seen from the Human-Chimpanzee Comparison

1: Only three orthologous genes. 2: Distribution of genes in cen and tel regions. 3: Quality and quantity of activating and inhibitory 4: Groups A and B KIR haplotypes. l

Abi-Rached et al 2010, PLoS Genetics

Evolution of the Interactions between MHC class I and Killer Immunoglobulin-like Receptors (KIR)

1.  Co-evolution of polymorphic MHC class I and variable NK cell receptors creates the species-specificity of NK-cell biology.

2.  The uniquely human NK-cell compromise between battling bugs and building bigger-brained babies.

3.  The quality of the modern human NK-cell response in non-African populations was improved by contributions from their older, more experienced Archaic relatives.

2DL4 3DL1/2

2DL7 2DL8 3DL5 3DL4 2DL9 3DS2

3DL3

2DL5 2DL6 3DS6

FCAR

2DS4

LILR

2DS1 2DS3/5 2DL5A 3DS1

2DL4 3DL2 FCAR

2DL5B 2DL2 2DS2 2DS3/5

2DL3 3DL1

3DL3 3DP1 2DL1 2DP1 LILR

2DS4

C1 C1

C1 C2 C2

C2

C2 C2 C2

C2 C2

E44 C2

C1 C1

Chimpanzee

Human

C1

C1

Humans Uniquely have Two Functionally Distinctive KIR Haplotype Groups: A (red genes) and B (blue genes)

1: Only three orthologous genes. 2: Distribution of genes in cen and tel regions. 3: Quality and quantity of activating and inhibitory 4: Groups A and B KIR haplotypes. l

Abi-Rached et al 2010, PLoS Genetics

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A BBBBBBA

Human A and B Groups of KIR Haplotypes: Why?

Parham & Guethlein 2010 J Clinical Investigation, Pyo et al PNAS 2011

Khakoo et al: Science 2004

Diseases Associated With Group A and B KIR Haplotypes

Hiby et al: J Exp Med 2004, JCI 2010

Infectious disease: hepatitis C virus Reproductive disease: pre-eclampsia

A haplotype good, B haplotype bad A haplotype bad, B haplotype good

Today’s Human Populations Carry The Strong Genetic Imprint from Selection by Pregnancy Disorder

Based on and extended from Hiby et al 2004, JEM.

Recurrent abortion: prevents reproduction Pre-eclamosia/ eclampsia: kills mother and child Fetal growth deficit: produces less viable offspring

Today’s Human Populations Carry The Strong Genetic Imprint from Selection by Pregnancy Disorder

Based on and extended from Hiby et al 2004, JEM.

Recurrent abortion: prevents reproduction Pre-eclampsia/ eclampsia: kills mother and child Fetal growth deficit: produces less viable/competitive offspring

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Battling Bugs and Building Babies: The Complementary Roles Played by the A and B KIR Haplotypes in Human Survival

Sex and War, Potts & Hayden 2008 Demonic Males, Peterson & Wrangham Sexual Coercion in Humans and Primates, Muller & Wrangham.

Parham unpublished

Yucpa Amerindians Have Low Overall Genetic Diversity Due to Serial Population Bottlenecks

Paul Norman

Yucpa have Balanced, Divergent A and B KIR Haplotypes

3DL3 2DS2 2DL3 2DL2 2DL1 2DS3 2DL4 3DL1 3DS1 2DS1 2DL5 2DS5 2DS4 3DL2

h1 46%

h2 47%

Infection

Reproduction

A

B

Gendzekhadze Norman et al. PNAS 2006

2DL4 3DL1/2

2DL7 2DL8 3DL5 3DL4 2DL9 3DS2

3DL3

2DL5 2DL6 3DS6

FCAR

2DS4

LILR

2DS1 2DS3/5 2DL5A 3DS1

2DL4 3DL2 FCAR

2DL5B 2DL2 2DS2 2DS3/5

2DL3 3DL1

3DL3 3DP1 2DL1 2DP1 LILR

2DS4

C1 C1

C1 C2 C2

C2

C2 C2 C2

C2 C2

E44 C2

C1 C1

Chimpanzee

Human

C1

C1

Unlike the Human KIR Family Chimpanzees do Not Have a Similar Compromise Between Defence and Reproduction

1: Only three orthologous genes. 2: Distribution of genes in cen and tel regions. 3: Quality and quantity of activating and inhibitory 4: Groups A and B KIR haplotypes. l

Abi-Rached et al 2010, PLoS Genetics

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Hypothesis: the Human-specific NK-cell compromise is the result of recent strong selection for bigger brains?

Parham, J. Exp.Med 2004

The C1 Epitope Originated at the MHC-B Locus, but in the Course of Human Evolution Most C1+ HLA-B

Allotypes were Lost or Discarded

HLA-­‐B*46  

25.4  19.8  17.1  14.8  12.7  10.6  8.3  5.6  1.8  0.0  

AF  (%)  

C1+ HLA-B*46 Formed by Gene Conversion in Modern Humans in South-East Asia and Spread Under Selection by Viral Infection?

Abi-Rached et al 2010 PLoS Genetics

Conclusions 1.  Under competing pressures from immune defence and reproduction,

variable NK-cell receptors and their MHC class I ligands evolve rapidly to become largely species-specific.

2.  Unique to the human species are the A and B KIR haplotypes that are under balancing selection as a consequence of the competing demands of immune, reproductive, and nervous systems.