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NK Kirs Structure Functions Carcassi Short

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NK Kirs Structure Functions Carcassi Short NK cells and KIRs: Structure and Functions Carlo Carcassi EFI-ASHI-APHIA Summer School 2013 Stintino 16 – 18 September 2013 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 HLA and KIRs 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 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 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. HLA class I and KIR: functionally related gene clusters exhibiting extreme polymorphism MICB MICA HLA-B HLA-A HLA-A HLA-C MHC chr. 6p21.3 HLA-E HLA-J HLA-F HLA-G HLA-H KIR ILT ILT GPVI ILT ILT NKp46 FCaR LAIR LRC chr. 19q13.4 Haplotype A 3DL3 2DL3 2DP1 2DL1 3DP1 2DL4 3DL1 2DS4 3DL2 Haplotype B 3DL3 2DS2 2DL2 3DP1 2DL4 3DS1 2DL5 2DS5 2DS1 3DL2 KIR gene organisation KIR gene organisation. The pseudoexon 3 and the deleted KIR3DP1 exon 2 is shown in red. KIR gene organisation 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 (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 (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 (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 KIR Diversity • Structural • Allelic • Haplotypic • Genotypic 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 http://www.ebi.ac.uk/ipd/kir/ Haplotypic diversity KIR Nomenclature – Haplotype • Basic set of 15 genes • 2DL2 and 2DL3 behave as alleles • 3DL1 and 3DS1 behave as alleles 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 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 Allelic variations of group A KIR haplotypes KIR receptor ligands HLA-Cwlys80 2DL1 2DS1 GROUP C2 (w2,4,5,6,707,1204, 15, 1602,17) HLA-Cwasn80 2DL2 2DL3 2DS2 GROUP C1 (w1,3,7,8,12,13,14, 1507,1601) 3DL1 3DS1 HLA-Bw4 3DL2 HLA-A3, -A11 2DL4 HLA-G KIR receptor ligands KIR receptor ligands 2005 KIR receptor ligands 1 KIR genotype Molecular intervention, vol 5, issue 4 August 2005 KIR Diversity Molecular intervention, vol 5, issue 4 August 2005 Why? Homozygosis/heterozygosis? Allelic polymorphism? Promoter activity? 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. KIR HAPLOTYPES INHERITANCE Raja Rajalingam: Korean J Hematol 2011;46:216-28. KIR HAPLOTYPES INHERITANCE Raja Rajalingam: Korean J Hematol 2011;46:216-28. 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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