The high susceptibility to infection in persons with Down Syndrome (DS) has led some investigators to explore the possibility of a defect in the immune system. Studies to date indicate no defect in humoral immunity suggesting that the defect might be in the cellular immune functions, but no specific defect has been found. Our investigation of the cellular immune system of adult DS patients was conducted by examining (1) the number and function of T-lymphocytes, (2) the phagocytic function of granulocytes, (3) the level of superoxide dismutase-1 (SOD-1) in leukocytes, and (4) the effects of SOD-1 on lymphocyte and granulocyte functions.

No description available.

This thesis presents genetic studies aiming at enlarging our knowledge regarding the genetic factors underlying two immune-mediated diseases, hypothyroidism and autoimmune Addison’s disease (AAD), in dogs and humans, respectively. Genetic and environmental factors are indicated to contribute to canine hypothyroidism, which can be considered a model for human Hashimoto’s thyroiditis (HT). In Paper I we performed the first genome-wide association (GWA) study of this disease in three high-risk dog breeds (Gordon Setter, Hovawart and Rhodesian Ridgeback). Using an integrated GWA and meta-analysis strategy, we identified a novel hypothyroidism risk haplotype located on chromosome 12 being shared by the three breeds. The identified haplotype, harboring three genes previously not associated with hypothyroidism, is independent of the dog leukocyte antigen region and significantly enriched across the affected dogs. In Paper II we performed a GWA study in another high-risk breed (Giant Schnauzer) and detected an associated locus located on chromosome 11 and conferring protection to hypothyroidism. After whole genome resequencing of a subset of samples with key haplotypes, we fine mapped the region of association that was subsequently screened for the presence of structural variants. We detected a putative copy number variant overlapping with the upstream region of the IFNA7 gene, which is located in a region of high genomic complexity. Remarkably, perturbed activities of type I Interferons have been extensively associated with HT and general autoimmunity. In Paper III we performed the first large-scale genetic study of human AAD, a rare autoimmune disorder characterized by dysfunction and ultimately destruction of the adrenal cortex. We resequenced 1853 immune-related genes comprising of their coding sequences, untranslated regions, as well as conserved intronic and intergenic regions in extensively characterized AAD patients and control samples, all collected in Sweden. We identified BACH2 gene as a novel risk locus associated with AAD, and we showed its independent association with isolated AAD. In addition, we confirmed the previously established AAD association with the human leukocyte antigen complex. The results of these studies will hopefully help increasing the understanding of such diseases in dogs and humans, eventually promoting their well-being.

Introduction: Canadian First Nations experience a significantly higher rate of Mycobacterium tuberculosis (MTB) infection than non-Indigenous Canadians. Th17 cells are a subset of CD4+ T cells that are distinguished by their production of Interleukin-17A (IL-17A), an important cytokine for defense against mycobacteria. IL-17 is a primary contributor to the formation and stabilization of the lung granuloma, a biological containment vessel to protect the host from tuberculosis (TB). Past research with First Nations people has identified single nucleotide polymorphisms (SNPs) in the Th1 and Th2 immune pathways may affect their disease risk. However, SNPs in key Th17 related genes and the P2RX7 gene have not been explored in First Nations despite their important role against infectious diseases. Hypothesis: This research hypothesizes that distinct First Nations groups (Dene, Cree and Saulteaux) will have a different frequencies of SNPs in the key Th17 immunity related genes (IL-17A, IL-17AR, IL-23R, and IFN-γR) and the P2RX7 gene, as compared to a non-Indigenous Canadian group. Methods: SNP profiles (IL-17A rs2275913, IL-17RA rs4819554, IL-23R rs10889677, IFN-γR rs2234711 and P2RX7 rs3751143) were identified through literature research and the NCBI database was used for identifying gene motifs, primer locations and Restriction Enzyme cut sites. Polymerase Chain Reaction and Restriction Fragment Length Polymorphism analysis was performed on and visualized on agarose gel to determine specific allele frequencies. Four different Manitoba First Nations communities; the Northern Dene (Dene 1 N=69. Dene 2 N=52), Central Cree (N=46), and Southern Saulteaux (N=56), participated in this research and their SNP profiles were compared to a non-Indigenous Canadian cohort (N=99). Results: Allele frequencies for IL-17A were statistically different for every First Nation community when compared to the non-Indigenous cohort (Dene 1 p=0.0043, Dene 2 p=0.0000, Cree p=0.0001, Saulteaux p=0.0000). Allele frequencies for IL-17RA were statistically different for every First Nation community except Saulteaux when compared to the non-Indigenous cohort (Dene 1 p=0.0000, Dene 2 p=0.0028, Cree p=0.0000). Allele frequencies for IL-23R were statistically different for Dene 1 and Saulteaux community when compared to the non-Indigenous cohort (Dene 1 p=0.0002, Saulteaux p=0.0000). Allele frequencies for IFN-R were statistically different for Cree community when compared to the non-Indigenous cohort (Cree p=0.0026). Allele frequencies for P2RX7 were statistically different for both Dene communities when compared to the non-Indigenous cohort (Dene 1 p=0.0000, Dene 2 p=0.0000). Conclusions: An effective Th17 response is required to bring Th1 cells to infected tissues and to balance inflammatory responses. Functional SNPs may compromise an appropriate immune response and contribute to disease. This study demonstrate that the non-Indigenous population maintained a significantly different genetic profile when compared to the First Nations populations. / October 2016

A inflamação é um componente essencial presente no microambiente tumoral, sendo relacionada a muitos tipos de câncer, como o de pulmão e de fígado. O objetivo foi estudar a influência de fatores genéticos relacionados à inflamação no desenvolvimento do câncer através da análise da progressão tumoral em camundongos AIRmax e AIRmin, geneticamente selecionados para máxima ou mínima resposta inflamatória. Os carcinomas foram induzidos pela injeção de Uretana ou DEN. 32 semanas após dose, a maioria dos AIRmax apresentaram tumores hepáticos, enquanto AIRmin foram resistentes. O contrário aconteceu com câncer de pulmão: todos os AIRmin foram acometidos e poucos AIRmax apresentaram pequenas lesões. As proteínas de fase aguda IL-6, TNF<font face=\"Symbol\">a e IL-1<font face=\"Symbol\">b são importantes nesse processo, pois tiveram aumento de produção em órgãos alvo horas após injeção. Esses resultados sugerem que um grupo de loci gênicos controla a resposta inflamatória e a susceptibilidade/resistência a diversos tipos de câncer e ressaltam o papel específico de células locais no controle da imunidade ao tumor. / Inflammatory components are an essential part of the tumor microenvironment being crucial in some types of cancer. Our objective was to study the influence of genetic factors relevant to inflammatory response regulation on cancer development by the comparative analysis of carcinogen-induced liver and lung tumors in AIRmax and AIRmin mouse strains, genetically selected for maximum and minimum inflammatory responsiveness. The carcinomas were induced by the injection of Urethane or DEN. 32 weeks after treatment, most AIRmax had liver tumors whereas AIRmin mice were resistant. The inverse occured in lungs: all AIRmin were affected and the incidence in AIRmax was 27.3%. The acute phase proteins IL-6, TNF<font face=\"Symbol\">a and IL-1<font face=\"Symbol\">b seem to be important in this process, with increased production in target organs hours after drug injection. These results provide a demonstration that a group of genes controls the inflammatory response and susceptibility or resistance to different types of cancers and also highlight the specific role of local cells in the control of tumor immunity.

A inflamação é um componente essencial presente no microambiente tumoral, sendo relacionada a muitos tipos de câncer, como o de pulmão e de fígado. O objetivo foi estudar a influência de fatores genéticos relacionados à inflamação no desenvolvimento do câncer através da análise da progressão tumoral em camundongos AIRmax e AIRmin, geneticamente selecionados para máxima ou mínima resposta inflamatória. Os carcinomas foram induzidos pela injeção de Uretana ou DEN. 32 semanas após dose, a maioria dos AIRmax apresentaram tumores hepáticos, enquanto AIRmin foram resistentes. O contrário aconteceu com câncer de pulmão: todos os AIRmin foram acometidos e poucos AIRmax apresentaram pequenas lesões. As proteínas de fase aguda IL-6, TNF<font face=\"Symbol\">a e IL-1<font face=\"Symbol\">b são importantes nesse processo, pois tiveram aumento de produção em órgãos alvo horas após injeção. Esses resultados sugerem que um grupo de loci gênicos controla a resposta inflamatória e a susceptibilidade/resistência a diversos tipos de câncer e ressaltam o papel específico de células locais no controle da imunidade ao tumor. / Inflammatory components are an essential part of the tumor microenvironment being crucial in some types of cancer. Our objective was to study the influence of genetic factors relevant to inflammatory response regulation on cancer development by the comparative analysis of carcinogen-induced liver and lung tumors in AIRmax and AIRmin mouse strains, genetically selected for maximum and minimum inflammatory responsiveness. The carcinomas were induced by the injection of Urethane or DEN. 32 weeks after treatment, most AIRmax had liver tumors whereas AIRmin mice were resistant. The inverse occured in lungs: all AIRmin were affected and the incidence in AIRmax was 27.3%. The acute phase proteins IL-6, TNF<font face=\"Symbol\">a and IL-1<font face=\"Symbol\">b seem to be important in this process, with increased production in target organs hours after drug injection. These results provide a demonstration that a group of genes controls the inflammatory response and susceptibility or resistance to different types of cancers and also highlight the specific role of local cells in the control of tumor immunity.

Lactic acid bacteria produce pediocin-like bacteriocins designated as Class Ha. These antimicrobial peptides are antagonistic against Listeria monocytogenes and other closely related Gram-positive bacteria Self-protection of the producer organism is attributed to the immunity proteins, encoded by genes that are eo-transcribed with the structural gene that encode the bacteriocin. The lactic acid bacterium, Leuconostoc gelidum UAL 187-22 is immune to its own bacteriocin, leucocin A. This is accredited to its immunity protein and the possible absence of a receptor on its cytoplasmic membrane. Leucocin A was purified from the supernatant of 1. gelidum to 90% purity by ion-exhange chromatography and C18 reverse phase High Pressure Liquid Chromatography (RP-HPLC) eluted with an acetonitrile, 0.1% Triflouroacetic acid (TFA) gradient. The immunity gene was isolated from the same producer using the polymerase chain reaction from the recombinant plasmid pJF 5.5 using primers EAL-2 and EAL-3. The amplicon was truncated into versions A and B by removing the C- and N-terminals, with HaeIII and ClaI restriction enzymes, respectively. The amplicon and the truncated fragments A and B were cloned into pMALc2 to construct recombinant plasmids pKPl, pKPIA and pKPIB, correspondingly, which were transformed into Escherichia coli (E. coli) strain JMI03. Clones were confirmed by colony PCR and Southern blot hybridization. The recombinant clones were subsequently expressed as MBP-IP, MBP-IPA and MBP-IPB fusion proteins that were verified by Western blot using the anti-MBP antibody. Factor Xa protease was used to cleave MBP from the proteins of interest. The resulting pure immunity protein versions had an approximate molecular weight of slightly more that 10 kDa. The binding interactions of the purified immunity protein constructs and leucocin A were compared on the Biacore 2000 instrument with surface plasmon resonance. None of the immunity constructs interacted with leucocin A, however, the N-terminal region of the immunity protein interacted with the cytoplasmic extract. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2008.

HIV-2 differs from HIV-1 in that many infected people experience normal survival, whilst only 20&percnt; progress rapidly to AIDS. Understanding mechanisms of delayed HIV-2 disease progression could provide new insights into HIV control. The Caio Community Cohort was established in Guinea-Bissau in the setting of high HIV-2 prevalence. This thesis investigates the role of polymorphic host restriction factors of the TRIM family in HIV-2 outcome. TRIM proteins are a family of E3 ubiquitin-ligases, where closely-related TRIM5&alpha; and TRIM22 are thought to inhibit HIV-1 transcription, uncoating and budding. There was an association between TRIM5&alpha; amino acid substitution R136Q and reduced HIV-2 viral load/prolonged survival. Conversely, P479L was enriched among HIV-2 infected participants and progressors with CD4+ T cell decline. TRIM22 was highly polymorphic in this cohort, revealing three novel coding variants. Although most substitutions were located in the putative virus-interacting PRYSPRY domain, two in the coiled-coil, D155N and R242T, showed significant and divergent associations with survival. R242T was enriched in HIV-2 infected participants, who progressed to death at twice the rate of wild-type controls. In silico studies predicted D282, D360, and R321 of TRIM22 to be highly conserved, exposed residues, for which polymorphisms would be deleterious. When aligned with sequences from the potent HIV-1 restriction factor, rhesus macaque TRIM5&alpha;, TRIM22 substitutions R321K, T415I, and D360Y were spatially relevant to residues involved in HIV-1 restriction. The role of TRIM22 in HIV restriction was supported by in vitro pilot studies showing that TRIM22 was upregulated by HIV-1 infection in a lymphoid cell line and co-localised with the HIV-1 capsid protein p24. Overexpression of TRIM22 resulted in the restriction of VSV-G pseudotyped HIV-1 and SIVmac. The R242T substitution diminished TRIM22's restriction of HIV-1 and SIVmac: protein analysis suggested that this may be due to the inability of the R242T mutant to fully dimerise.

<p>U&nbsp; ovom&nbsp; radu&nbsp; sagledan&nbsp; je&nbsp; molekularni&nbsp; diverzitet,&nbsp; filogeografska&nbsp; struktura,<br />prostorna&nbsp; distribucija&nbsp; molekularnog&nbsp; diverziteta,&nbsp; kao&nbsp; i&nbsp; prisustvo&nbsp; selekcionih<br />signala i genetičkih signala lokalnih adaptacija kod 251 jedinke&nbsp; vrste&nbsp; Lepus<br />europaeus (Pallas,&nbsp; 1778)&nbsp; sa&nbsp; teritorije&nbsp; Evrope&nbsp; i&nbsp; Bliskog&nbsp; Istoka,&nbsp; a&nbsp; na&nbsp; osnovu<br />analize&nbsp; varijabilnosti&nbsp; sekvenci&nbsp; D&nbsp; petlje&nbsp; mtDNK, MT-ND2,&nbsp; MT-ND6,&nbsp; MHCDQA, MHC-DQB i TLR2 gena. Uočen je visok nivo parametara molekularnog<br />diverziteta&nbsp; za&nbsp; sve&nbsp; ispitivane&nbsp; molekularne&nbsp; markere.&nbsp; Utvrđeno&nbsp; je&nbsp; postojanje<br />filogeografske&nbsp; strukturiranosti&nbsp; vrste&nbsp; na&nbsp; osnovu&nbsp; mtDNK,&nbsp; kao&nbsp; i&nbsp; asimetričan<br />protok gena jedinki sa teritorije Anadolije na teritoriju Balkana&nbsp; na osnovu D<br />petlje mtDNK, MT-ND2 i MT-ND6 gena, dok je na osnovu sekvenci D petlje<br />mtDNK uočena gotovo tri puta veća stopa protoka gena sa Balkana u centralnu<br />i&nbsp; zapadnu&nbsp; Evropu.&nbsp; Utvrđeno&nbsp; je&nbsp; prisustvo&nbsp; signala&nbsp; poizivne&nbsp; selekcije&nbsp; u&nbsp; okviru<br />MT-ND6&nbsp; gena,&nbsp; kao&nbsp; i&nbsp; efekat&nbsp; klimatskih&nbsp; parametara&nbsp; (precipitacije)&nbsp; na<br />distribuciju&nbsp; proteinskih&nbsp; varijanti&nbsp; ND6C&nbsp; i&nbsp; ND6F,&nbsp; kao&nbsp; moguća&nbsp; posledica<br />regionalnih adaptacija na razlike u sredinskim uslovima. Pokazano je odsustvo<br />signala&nbsp; filogeografske&nbsp; strukturiranosti&nbsp; na&nbsp; osnovu MHC-DQA, MHC-DQB i<br />TLR2 gena.&nbsp; Uočeno&nbsp; je&nbsp; postojanje&nbsp; prostorne&nbsp; strukturiranosti&nbsp; na&nbsp; osnovu&nbsp; gena<br />imunskog&nbsp; sistema,&nbsp; i&nbsp; definisane&nbsp; su&nbsp; dve&nbsp; prostorne&nbsp; grupe,&nbsp; jedna&nbsp; koja&nbsp; je<br />obuhvatala&nbsp; jedinke&nbsp; sa&nbsp; teritorije&nbsp; Bliskog&nbsp; Istoka,&nbsp; i&nbsp; druga&nbsp; koja&nbsp; je&nbsp; obuhvatala<br />jedinke&nbsp; sa&nbsp; teritorije&nbsp; Evropi.&nbsp; Vi&scaron;e&nbsp; vrednosti&nbsp; parametara&nbsp; molekularnog<br />diverziteta uočene su u anadolijskoj grupi, u poređenju sa evropskom grupom.<br />Uočen je signal delovanja pozitivne i negativne selekcije u MHC-DQA i MHCDQB genima, kao i signal negativne selekcije u TLR2 genu. Pokazan je efekat<br />klimatskih&nbsp; parametara&nbsp; na&nbsp; distribuciju&nbsp; najzastupljenijih&nbsp; proteinskih&nbsp; varijanti<br />MHC-DQA&nbsp; i&nbsp; MHC-DQB&nbsp; gena kao&nbsp; indirektni&nbsp; pokazatelj&nbsp; imunogenetičkih<br />adaptacija&nbsp; na&nbsp; sredinski&nbsp; uslovljene&nbsp; pretpostavljene&nbsp; razlike&nbsp; u&nbsp; distribuciji<br />patogena.&nbsp; Mehanizam&nbsp; oblikovanja&nbsp; varijabilnosti&nbsp; MHC&nbsp; gena&nbsp; rezultat&nbsp; je<br />uzajamnog delovanja mutacija, rekombinacija i selekcije.</p> / <p>In&nbsp; this&nbsp; doctoral&nbsp; dissertation,&nbsp; molecular&nbsp; diversity,&nbsp; phylogeographic&nbsp; structure,<br />spatial&nbsp; distribution&nbsp; of&nbsp; molecular&nbsp; diversity,&nbsp; detection&nbsp; of&nbsp; possible&nbsp; selection<br />signals&nbsp; shaping&nbsp; the&nbsp; evolution of&nbsp; these&nbsp; genes,&nbsp; as&nbsp; well&nbsp; as&nbsp; the&nbsp; presence&nbsp; of<br />local/regional&nbsp; adaptations&nbsp; in&nbsp; correlation&nbsp; was&nbsp; examined&nbsp; in&nbsp; 251&nbsp; brown&nbsp; hares<br />from&nbsp; Europe&nbsp; and&nbsp; the&nbsp; Middle East&nbsp; based&nbsp; on&nbsp; the&nbsp; analyses&nbsp; of&nbsp; mitochondrial&nbsp; D<br />loop,&nbsp; mitochondrially&nbsp; Encoded&nbsp; NADH&nbsp; Dehydrogenase&nbsp; 2&nbsp; (MT-ND2),<br />mitochondrially&nbsp; Encoded&nbsp; NADH&nbsp; Dehydrogenase&nbsp; 6&nbsp; (MT-ND6),&nbsp; exon&nbsp; 2&nbsp; of<br />MHC Class II genes MHC-DQA,MHC-DQB and Toll Like Receptor 2 (TLR2)<br />gene sequences. A high level of molecular diversity was found based on the all<br />applied&nbsp; markers.&nbsp; Strong&nbsp; signal&nbsp; of&nbsp; phylogeographical&nbsp; and&nbsp; spatial&nbsp; structuring<br />was&nbsp; observed&nbsp; for&nbsp; mtDNA,&nbsp; most&nbsp; likely&nbsp; as&nbsp; a&nbsp; consequence&nbsp; of&nbsp; climatic<br />perturbations&nbsp; during&nbsp; the&nbsp; Pleistocene.&nbsp; The&nbsp; evolutionary&nbsp; development&nbsp; of&nbsp; hares<br />from&nbsp; Anatolia/Israel&nbsp; to&nbsp; the&nbsp; Balkans,&nbsp; and&nbsp; furthermore&nbsp; to&nbsp; central&nbsp; and&nbsp; western<br />Europe was suggested by several lines of evidences, which include dating the<br />population&nbsp; demography&nbsp; based&nbsp; on&nbsp; D-loop&nbsp; sequences,&nbsp; the&nbsp; observed&nbsp; migration<br />patterns,&nbsp; results&nbsp; of&nbsp; demographic&nbsp; tests,&nbsp; and&nbsp; apparent&nbsp; reduction&nbsp; in&nbsp; molecular<br />diversity&nbsp; indices&nbsp; along&nbsp; this&nbsp; trajectory.&nbsp; Positive&nbsp; selection&nbsp; acting&nbsp; on MT-ND6<br />gene&nbsp; was&nbsp; detected,&nbsp; together&nbsp; with&nbsp; significant&nbsp; climatic&nbsp; effect&nbsp; shaping&nbsp; the<br />distribution&nbsp; of&nbsp; the&nbsp; most&nbsp; prevalent&nbsp; protein&nbsp; variants&nbsp; found&nbsp; in&nbsp; this&nbsp; gene,<br />supposedly&nbsp; as&nbsp; a&nbsp; consequence&nbsp; to&nbsp; local/regional&nbsp; adaptations&nbsp; due&nbsp; to&nbsp; the<br />environmentally induced different energetic requirements and optimization of<br />OXPHOS&nbsp; genes.&nbsp; On&nbsp; the&nbsp; other&nbsp; side,&nbsp; less&nbsp; evident&nbsp; phylogeographic&nbsp; signal&nbsp; and<br />absence&nbsp; of&nbsp; strong&nbsp; structuring&nbsp; was&nbsp; revealed&nbsp; in&nbsp; MHC&nbsp; genes.&nbsp; High&nbsp; diversity&nbsp; at<br />MHC genes seems to be shaped by the interplay of recombination, selection<br />mechanisms&nbsp; and&nbsp; adaptations.&nbsp; Balancing&nbsp; selection&nbsp; seems&nbsp; to&nbsp; maintain&nbsp; a&nbsp; high<br />molecular&nbsp; diversity&nbsp; within&nbsp; these&nbsp; genes,&nbsp; while&nbsp; directional selection&nbsp; promotes<br />local/regional adaptations to pathogenic landscapes, as indirectly suggested by<br />a&nbsp; significant&nbsp; effect&nbsp; of&nbsp; climatic&nbsp; parameters&nbsp; on&nbsp; the&nbsp; distribution&nbsp; of&nbsp; protein<br />variants in both examined MHC genes.</p>

L’idée qu’une cellule puisse effectuer la cytolyse de cellules transformées, comme une cellule Natural Killer (NK), tout en ayant la capacité de présenter des antigènes, comme une cellule dendritique (DC), peut sembler fantaisiste. Cependant, de telles cellules furent bel et bien identifiées chez la souris en 2006. Ces cellules, nommées Interferon-producing Killer Dendritic Cells (IKDC), furent l’objet d’une caractérisation extensive qui révéla leur énorme potentiel immunologique. La combinaison de fonctions associées à des cellules NK et à des DC a doté les IKDC d’un pouvoir antitumoral remarquable. D’ailleurs, il a été démontré que les IKDC sont plus efficaces que les cellules NK pour limiter la croissance tumorale. Ainsi, suite à leur découverte, les IKDC ont suscité beaucoup d’intérêt. Cependant, une controverse émergea sur la nature des IKDC. Plusieurs groupes indépendants tentèrent de reproduire les expériences attestant les fonctions de DC des IKDC, sans y parvenir. De plus, des études additionnelles révélèrent que les IKDC possèdent des similitudes très importantes avec les cellules NK. Ces observations ont mené la communauté scientifique à suggérer que les IKDC sont des cellules NK en état d’activation (aNK). Malgré cette controverse, les caractéristiques antitumorales des IKDC sont si uniques et considérables qu’il est primordial de poursuivre l’étude de ces cellules. Pour y arriver, il est essentiel de déterminer la nature des IKDC et de mettre fin à ce débat. Par la suite, il sera important d’identifier des façons de cibler spécifiquement les IKDC pour permettre leur usage dans le cadre de thérapies antitumorales. Ainsi, l’objectif de cette thèse est de définir l’identité des IKDC, puis de déterminer les facteurs génétiques responsables de la régulation de ces cellules. Nous avons démontré que les IKDC ne sont pas des cellules aNK, contrairement à ce qui avait été suggéré. Nous avons constaté que les IKDC prolifèrent activement et possèdent un phénotype unique, des caractéristiques associées à des cellules NK très immatures. Afin de déterminer si les IKDC peuvent acquérir un phénotype mature, nous avons effectué des expériences de transfert adoptif. Suite à leur injection in vivo, les IKDC acquièrent un phénotype de cellules matures, mais étonnamment, elles se différencient aussi en cellules NK. Ainsi, nous avons révélé que les IKDC sont un intermédiaire dans la différenciation des cellules NK. En parallèle, nous avons démontré que la proportion d’IKDC varie grandement entre des souris de fond génétique différent, indiquant que des facteurs génétiques sont impliqués dans la régulation de ces cellules. Nous avons alors effectué une analyse génétique qui a révélé que les IKDC sont régulées par des facteurs génétiques compris dans une région distale du chromosome 7. Les résultats présentés dans cette thèse constituent une avancée importante pour la recherche sur les IKDC. Ils ont permis de définir la nature des IKDC et d’identifier un intervalle génétique impliqué dans la régulation de ces cellules. Ces découvertes sont des connaissances précieuses pour l’identification des IKDC chez l’Homme et la création de nouvelles thérapies dans la lutte contre le cancer. / The idea that a cell could kill transformed cells, like a Natural Killer (NK) cell, all the while exhibiting also the capacity to present antigens to T cells, like a Dendritic Cell (DC), may seem farfetched. However, in mice, a cell presenting these specific properties was identified in 2006. These cells were named Interferon-producing Killer Dendritic Cells (IKDC) and extensive studies revealed that they were endowed with an important immunological potential. Indeed, the fact that IKDCs exhibit properties of both DC and NK cells conferred them with an exceptional anti-tumor potential. Notably, on a per cell basis, the in vivo anti-tumor activity of IKDCs is more efficient than NK cells. Therefore, following their identification, IKDCs showed great therapeutic promise. However, a debate on the cell lineage origin of IKDCs emerged. Several independent groups could not replicate the finding that IKDCs showed functional antigen-presentation properties similar to DCs. Also, additional studies revealed that IKDCs are very similar to NK cells. These and other observations led the scientific community to believe that IKDCs were activated NK cells. Despite this controversy, IKDCs clearly exhibit a unique and outstanding anti-tumor potential, highlighting the relevance to further explore these cells. We must first close the debate regarding the lineage origin of IKDCs. We subsequently need to identify a means to specifically target IKDCs to facilitate their use in novel anti-tumor therapies. Thus, the objective of my thesis is first, to define the identity of IKDCs and second, to determine the genetic factors implicated in the regulation of these cells. For the first objective, we demonstrated that IKDCs do not represent activated NK cells, as previously suggested. We show that IKDCs are highly proliferative and exhibit a unique phenotype associated with very immature NK cells. In an attempt to verify if IKDCs could acquire a mature phenotype, we conducted an adoptive transfer experiment. We found that, after adoptive transfer, IKDCs adopt a mature phenotype, but also surprisingly differentiate into NK cells. These findings indicate that IKDCs represent an intermediate in NK-cell differentiation. For the second objective, we demonstrated that the IKDC proportion was highly variable between strains of different background origins, indicating that these cells are regulated by genetic factors. A genetic study revealed that genetic factors in distal arm of chromosome 7 associate with the proportion of IKDCs. The results presented in this thesis represent an important breakthrough for the research on IKDCs. They allowed to define the cell lineage origin of IKDCs and to identify a genetic region involved in the regulation of this cell type. These discoveries are valuable knowledge for the identification of human IKDCs and the development of novel anti-tumor therapies.