Variations in killer-cell immunoglobulin-like receptor and human leukocyte antigen genes and immunity to malaria

Malaria is one of the deadliest infectious diseases in the world. Immune responses to Plasmodium falciparum malaria vary among individuals and between populations. Human genetic variation in immune system genes is likely to play a role in this heterogeneity. Natural killer (NK) cells produce inflammatory cytokines in response to malaria infection, kill intraerythrocytic Plasmodium falciparum parasites by cytolysis, and participate in the initiation and development of adaptive immune responses to plasmodial infection. These functions are modulated by interactions between killer-cell immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA). Therefore, variations in KIR and HLA genes can have a direct impact on NK cell functions. Understanding the role of KIR and HLA in immunity to malaria can help to better characterize antimalarial immune responses. In this review, we summarize the different KIR and HLA so far associated with immunity to malaria.This work was supported through the DELTAS Africa Initiative (Grant no. 107743), that funded Stephen Tukwasibwe through PhD fellowship award, and Annettee Nakimuli through group leader award. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Science (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (Grant no. 107743) and the UK government. Francesco Colucci is funded by Wellcome Trust grant 200841/Z/16/Z. The project received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 695551) for James Traherne and John Trowsdale. Jyothi Jayaraman is a recipient of fellowship from the Centre for Trophoblast Research

Ontology Population Framework of MAGNETO for Instantiating Heterogeneous Forensic Data Modalities

© 2019, IFIP International Federation for Information Processing. The growth in digital technologies has influenced three characteristics of information namely the volume, the modality and the frequency. As the amount of information generated by individuals increases, there is a critical need for the Law Enforcement Agencies to exploit all available resources to effectively carry out criminal investigation. Addressing the increasing challenges in handling the large amount of diversified media modalities generated at high-frequency, the paper outlines a systematic approach adopted for the processing and extraction of semantic concepts formalized to assist criminal investigations. The novelty of the proposed framework relies on the semantic processing of heterogeneous data sources including audio-visual footage, speech-to-text, text mining, suspect tracking and identification using distinctive region or pattern. Information extraction from textual data, machine-translated into English from various European languages, uses semantic role labeling. All extracted information is stored in one unifying system based on an ontology developed specifically for this task. The described technologies will be implemented in the Multimedia Analysis and correlation enGine for orgaNised crime prEvention and invesTigatiOn (MAGNETO)

Early primed KLRG1- CMV-specific T cells determine the size of the inflationary T cell pool

Memory T cell inflation is a process in which a subset of cytomegalovirus (CMV) specific CD8 T cells continuously expands mainly during latent infection and establishes a large and stable population of effector memory cells in peripheral tissues. Here we set out to identify in vivo parameters that promote and limit CD8 T cell inflation in the context of MCMV infection. We found that the inflationary T cell pool comprised mainly high avidity CD8 T cells, outcompeting lower avidity CD8 T cells. Furthermore, the size of the inflationary T cell pool was not restricted by the availability of specific tissue niches, but it was directly related to the number of virus-specific CD8 T cells that were activated during priming. In particular, the amount of early-primed KLRG1- cells and the number of inflationary cells with a central memory phenotype were a critical determinant for the overall magnitude of the inflationary T cell pool. Inflationary memory CD8 T cells provided protection from a Vaccinia virus challenge and this protection directly correlated with the size of the inflationary memory T cell pool in peripheral tissues. These results highlight the remarkable protective potential of inflationary CD8 T cells that can be harnessed for CMV-based T cell vaccine approaches

Asymmetric cell division shapes naive and virtual memory T-cell immunity during ageing

Efficient immune responses rely on heterogeneity, which in CD8+ T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8+ T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8+ T cells reveals that virtual memory cells (TVM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8+ T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing

Maintenance of effector-memory Maxi CD8 T cells is dependent on IL-15 but independent of IL-7 or IL-2.

<p>(A) Naïve Maxi CD8 T cells were adoptively transferred into naïve C57BL/6 mice followed by i. v. MCMVΔm157 infection. Effector-memory Maxi T cells were sorted from the lungs and transferred into C57BL/6 recipients or knockout recipients. Recipients were administered i.p. during 30 days with receptor-blocking or cytokine neutralising antibodies every second day. Total numbers of Maxi cells were assessed in the lungs at 4 weeks post transfer. (B) Percentage of recovered Maxi cells normalized to untreated control is shown as mean + SEM of n = 4–12 mice pooled from five independent experiments. (C) Representative Bcl-2 histogram gated on Maxi CD8 T cells. (D) Mean fluorescence intensities of Maxi CD8 T cells are shown as mean + SEM of n = 4 mice representative of two independent experiments. (E) Mean fluorescence intensities of pSTAT5 in inflationary Maxi cells are shown as mean + SEM of n = 6 mice pooled from two independent experiments. (F) Representative Bcl-2 histogram gated on Maxi CD8 T cells and mean fluorescence intensities of Bcl-2 in inflationary Maxi cells are shown as mean + SEM of n = 6 mice pooled from two independent experiments. (B, D-F) *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. Statistical analyses were performed using the non-parametric Mann-Whitney <i>U</i> test.</p

Tissue maintenance of CMV-specific inflationary memory T cells by IL-15

<div><p>Cytomegalovirus (CMV) infection induces an atypical CD8 T cell response, termed inflationary, that is characterised by accumulation and maintenance of high numbers of effector memory like cells in circulation and peripheral tissues—a feature being successfully harnessed for vaccine purposes. Although stability of this population depends on recurrent antigen encounter, the requirements for prolonged survival in peripheral tissues remain unknown. Here, we reveal that murine CMV-specific inflationary CD8 T cells are maintained in an antigen-independent manner and have a half-life of 12 weeks in the lung tissue. This half-life is drastically longer than the one of phenotypically comparable inflationary effector cells. IL-15 alone, and none of other common γ-cytokines, was crucial for survival of inflationary cells in peripheral organs. IL-15, mainly produced by non-hematopoietic cells in lung tissue and being trans-presented, promoted inflationary T cell survival by increasing expression of Bcl-2. These results indicate that inflationary CD8 T cells are not just simply effector-like cells, rather they share properties of both effector and memory CD8 T cells and they appear to be long-lived cells compared to the effector cells from acute virus infections.</p></div

Maintenance of inflationary CD8 T cells is impaired in IL-15Rα deficient hosts.

<p>Naïve Maxi CD8 T cells were adoptively transferred into naïve C57BL/6 mice one day prior to MCMV infection. During latency, Maxi T_EM cells were sorted from lungs and adoptively transferred into IL-15Rα knockout animals. Recovery of Maxi T cells was assessed in the lungs four weeks post transfer. (A) Percentage of recovered Maxi cells in the lungs normalised to Cre-negative recipients is shown in CMV-Cre <i>Il15ra</i>^fl/fl mice as mean + SEM of n = 12 mice pooled from two independent experiments. (B) Mean fluorescence intensity of Bcl-2 in Maxi cells from the lungs are shown as mean + SEM of n = 6–8 mice representative of two independent experiments. (A-B) ***p<0.001. Statistical analyses were performed using the non-parametric Mann-Whitney <i>U</i> test.</p

IL-15 ablation in non-hematopoietic cells reduces inflationary T cell maintenance.

<p>(A) Lung lymphocytes were isolated from naïve C57BL/6 mice and sorted according to CD45 staining. Relative <i>Il15</i> mRNA levels normalized to β-actin internal controls was calculated using the ΔΔC_T method, shown as mean + SEM of n = 6 mice pooled from two independent experiments. (B) Experimental setup: Naïve IL-15^-/- and Thy1.1 mice were lethally irradiated and reconstituted with indicated bone marrow cells. Inflationary Maxi T_EM cells were sorted from lungs of latently infected donor mice and transferred into the chimeras. The total numbers of Maxi cells were assessed four weeks post transfer. Total numbers of Maxi CD8 T cells in lungs (C), and spleen (D) at four weeks post transfer are shown as mean + SEM of n = 12–15 mice pooled from three independent experiments. (A; C-D); *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001. Statistical analyses were performed using the non-parametric Mann-Whitney <i>U</i> test.</p

Inflationary T_EM P14 cells have a longer half-life than effector P14 CD8 T cells.

<p>(A) Naïve P14 CD8 T cells were adoptively transferred into naïve C57BL/6 mice followed by i. v. infection with MCMV-M45-gp33 for acute P14 T_EFF or MCMV-ie2-gp33 for latent P14 T_EM. Effector P14 T cells (7 dpi) and T_EM P14 cells (> 60 dpi) were sorted from the lungs and transferred into naïve recipients. (B) Left graph: Effector P14; Right graph: T_EM P14. Percentage recovered P14 cells from the lungs normalized to <1 week time point is shown as mean + SEM of n = 10 mice pooled from two independent experiments. (C) Representative histograms of T_EFF and T_EM P14 T cell population from the lung tissues are shown. Mean fluorescence intensities of Bcl-2 of P14 cells (7 dpi) and P14 (> 60 dpi) are shown as mean + SEM of n = 4–5 mice representative from two independent experiments. (A, B); **p<0.01. Statistical analyses were performed using the non-parametric Mann-Whitney U test.</p