nk cells and kirs: structure and functionss/iss_sep_2013_carcassi_nk_kir.pdf · nk cells and kirs:...
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NK cells and KIRs: Structure and Functions
EFI-ASHI-APHIA Summer School 2013 Stintino
16 – 18 September 2013
Carlo Carcassi
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Natural Killer cells (NK) • About 10% of lymphocytes
(CD56+CD3-) • Kill target cells
(e. g. leukemic blasts, infected cells)
• Are regulated by specific receptors (e.g. KIRs)
• Produce immunoregulatory cytokines (e.g. IFN-γ)
• Regulate immune response
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HLA class I molecules have a double function: - interact with NK cells in innate immune response and - with cytolytic T cells in adaptative immune response
HLA and KIRs
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KIRs: what are they and where are they expressed?
They are a family of transmembrane glycoproteins
They are expressed on NK cells and a subset of T lymphocytes
What do they do?
They are key regulators of NK-cell development, tolerance and activation
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Why are they so important?
Many studies have demonstrated a role for combinations of KIR receptors and their HLA Class I
ligands in a variety of diseases such as viral infections, autoimmune disorders and tumors.
Certain KIR-HLA combinations can influence pregnancy, hematopoietic stem cell transplantation
and also organ transplantation.
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chr. 19q13.4
ILT
ILT
LAIR
KIR
FCaR
NK
p46
GPV
I
LRC
HLA class I and KIR: functionally related gene clusters exhibiting extreme polymorphism
chr. 6p21.3 MHC M
ICB
M
ICA
HLA
-B
HLA
-C
HLA
-J
HLA
-E
HLA
-A
HLA
-G
HLA
-F
HLA
-H
3DL3 2DL3 2DP1 2DL1 3DP1 Haplotype A
2DL4 2DS4 3DL2 3DL1
3DL3 2DS2 2DL2 2DL4 3DP1 2DL5 2DS1 3DL2 2DS5 3DS1 Haplotype B
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KIR gene organisation
KIR gene organisation. The pseudoexon 3 and the deleted KIR3DP1 exon 2 is shown in red.
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KIR gene organisation
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The KIR gene products attain a high level of diversity
based upon four levels of variation:
(1) the product of each KIR gene specifically recognizes a
distinct subset of the available MHC-I allotypes
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(2)
different combinations of the 14 KIR genes are
inherited as distinct haplotypes by individuals within
the human population, and different haplotypes can
vary in proportion of activating and inhibitory KIR
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(3)
many distinct alleles of individual KIR genes have arisen
through point mutations encoding minor sequence
variations of one to several amino acids, which can
affect receptor surface expression level,
recognition by anti-KIR antibodies, and
affinity/avidity for MHC-I
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(4)
diversity of the NK cell repertoire in peripheral
blood is generated through the stochastic
expression of different combinations of the
available KIR gene products on the surface of
individual NK cells
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KIR Diversity • Structural
• Allelic
• Haplotypic
• Genotypic
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KIR protein structures
KIR2DL4 is the unique long tail activating KIR, only expressed on CD56
high NK cells, stimulating a more potent activation of cytokine production
rather than cytotoxicity and associated with
FCεRI-γ adaptor instead of DAP12
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http://www.ebi.ac.uk/ipd/kir/
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Haplotypic diversity
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KIR Nomenclature – Haplotype • Basic set of 15 genes
• 2DL2 and 2DL3 behave as alleles
• 3DL1 and 3DS1 behave as alleles
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KIR Nomenclature - Haplotype • Each KIR haplotype has an official name:
KH-001 or KH-022B • The A or B indicating whether the haplotype
belonged to the A or the B group • Followed with a optional 17 digit binary code
indicating the presence or absence of each gene
• KH-001-11100010011011011
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Ligand unknown. Some alleles of 2DS4 have a 22bp deletion, the null allele has a population frequency of about 84% (allele frequency of 60%).
2DL4 may transmit inhibitory, stimulatory, or both types of signals. 2DL4 binds to HLA-G. Framework KIR gene
About 50% of the population espress only type A haplotypes -> inhibitory
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Allelic variations of group A KIR haplotypes
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KIR receptor ligands
2DL1 2DS1 HLA-Cwlys80
GROUP C2 (w2,4,5,6,707,1204,
15, 1602,17)
3DL1 3DS1 HLA-Bw4 3DL2 HLA-A3, -A11
2DL4 HLA-G
2DL2 2DL3 2DS2 HLA-Cwasn80
GROUP C1 (w1,3,7,8,12,13,14,
1507,1601)
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KIR receptor ligands
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KIR receptor ligands 2005
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KIR receptor ligands
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Molecular intervention, vol 5, issue 4 August 2005
1 KIR genotype
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KIR Diversity
Molecular intervention, vol 5, issue 4 August 2005
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Why? Homozygosis/heterozygosis?
Allelic polymorphism?
Promoter activity?
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Only 45 % of HLA-A alleles are ligands recognized by KIRs Only 36 % of HLA-B alleles are ligands recognized by KIRs All HLA-C alleles present C1 o C2 epitopes.
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Raja Rajalingam: Korean J Hematol 2011;46:216-28.
KIR HAPLOTYPES INHERITANCE
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Raja Rajalingam: Korean J Hematol 2011;46:216-28.
KIR HAPLOTYPES INHERITANCE
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NK cells thus make vital contributions to the immune system and the reproductive system. The former being essential for day-to-day survival of human individuals. The latter for the generation to generation survival of human populations and the human species
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