Cognate Recognition Research Articles

Thioreductase-Containing Epitopes Inhibit the Development of Type 1 Diabetes in the NOD Mouse Model.

Autoreactive CD4+ T cells recognizing islet-derived antigens play a primary role in type 1 diabetes. Specific suppression of such cells therefore represents a strategic target for the cure of the disease. We have developed a methodology by which CD4+ T cells acquire apoptosis-inducing properties on antigen-presenting cells after cognate recognition of natural sequence epitopes. We describe here that inclusion of a thiol-disulfide oxidoreductase (thioreductase) motif within the flanking residues of a single MHC class II-restricted GAD65 epitope induces GAD65-specific cytolytic CD4+ T cells (cCD4+ T). The latter, obtained either in vitro or by active immunization, acquire an effector memory phenotype and lyse APCs by a Fas–FasL interaction. Furthermore, cCD4+ T cells eliminate by apoptosis activated bystander CD4+ T cells recognizing alternative epitopes processed by the same APC. Active immunization with a GAD65 class II-restricted thioreductase-containing T cell epitope protects mice from diabetes and abrogates insulitis. Passive transfer of in vitro-elicited cCD4+ T cells establishes that such cells are efficient in suppressing autoimmunity. These findings provide strong evidence for a new vaccination strategy to prevent type 1 diabetes.

Abstract IA28: Immunological insights from tracking dynamic cellular behavior in lymph nodes and tissues

Abstract A unique feature of the vertebrate immune system is its dependency on the migratory capacity of individual immune cells for proper development, differentiation and functional execution in vivo. High-resolution dynamic live-animal imaging has allowed scientists to decipher novel immunological insights, which is aided by increasing imaging sophistication, availability of in vivo experimental models, and high throughput multi-parameter data collection and analyses. Intravital imaging, combined with mathematical modeling and other immunological tools, has revealed an asymmetric role for MHC interactions in modulating CD4+ vs. CD8+ T lymphocyte surveillance strategies for cognate antigens in lymph nodes (LNs) [1]. Furthermore, naïve CD8+ T cells are preferentially attracted in a CCR5-dependent manner to LN niche sites where cognate antigen recognition occurs between DCs and CD4+ T cells via CCL3 / CCL4 gradient [2]. Additional data suggest that naïve CD8+ T cells regulate transient expression of preformed inflammatory chemokine receptors via integrin engagement early upon entry into inflamed LNs, suggesting a context-specific orchestration of immune responses in LNs. Once activated in the LNs, T cells travel to various anatomic compartments for delivery of their acquired effector function. Recent imaging experiments revealed that extravascular, CNS-resident CX3CR1+ APCs dynamically extend their cellular processes across intact vessel wall into vascular lumen. The frequency of projections increased in experimental autoimmune encephalomyelitis (EAE), whereas the number of projections remained stable compared to baseline days after other tissue injury such as CNS tumor infiltration and aseptic spinal cord trauma [3]. This unique behavior by CNS parenchymal CX3CR1+ cells may represent their unexplored functional role in antigen sampling and immune cell recruitment across the BBB. Lastly, we reported a novel role for cyclin-dependent kinase 5 (Cdk5), a proline-directed serine-threonine kinase, in T cell activation and persistence [4]. Cdk5 enzymatic activity has been found to be aberrantly up-regulated in a wide spectrum of tumors. Disruption of Cdk5 activity sensitizes tumor cells to elimination in a T cell-dependent manner, a process that is associated with an attenuated response in PD-L1 up-regulation upon interferon-γ exposure. Our additional emerging data further support a synergistic role of anti-Cdk5 agents in modulating tumor sensitivity to immunotherapeutic approaches. In conclusion, the tissue microenvironment plays a critical role in regulating host immune cell tumor crosstalk, and recent new advances in imaging modalities and in vivo experimental methodologies provided new insights that hold promises to propel the field of cancer immunotherapy forward.

Antigen-dependent and -independent contributions to primary memory CD8 T cell activation and protection following infection.

Memory CD8 T-cell activation, including expression of IFN-γ and granzymeB, can be induced by antigen (Ag)-dependent signals through the T-cell-receptor, or by pathogen-derived inflammatory cytokines in an Ag-independent manner. Recent studies have come to conflicting results regarding the contributions of Ag and/or inflammation to memory CD8 T-cell activation. Additionally, research has indicated that inflammation-driven CD8 T-cell responses during un-related infections (bystander activation) have the potential to provide protection, but whether protection occurs in immuno-competent hosts is unclear. To investigate these questions, we examined activation of virus-specific memory CD8 T-cells following infection with L. monocytogenes either expressing or not cognate Ag. We show that Ag and inflammation act synergistically in vitro to induce memory activation. In vivo, we found that when memory CD8 T-cells significantly contribute to clearance of infection, early activation and continued responses by these cells are enhanced by cognate Ag recognition. Mechanistically, we show that bystander responses by memory are dependent upon the dose of infection and the amount of inflammation elicited following infection and are able to provide protection in IFN-γ deficient mice, but not in immuno-competent hosts. The data elucidate the requirements for memory CD8 T-cell activation and the protective role of bystander responses.

The role of explicit instruction in cross-script cognate recognition: The case of Ukrainian-speaking EAP learners

This study aims to determine to what extent the following 90-minute classroom interventions facilitate the acquisition of Ukrainian-English cognates: (i) explicit instruction (EI) and elaborative processing (Craik, 2002; Hulstijn, 2003) and (ii) reading texts containing a sizeable number of cognates (RC). Two intact classes of an English-for-Academic-Purposes (EAP) course at a Ukrainian university underwent EI and RC treatments respectively, while a third served as a Control group. A comparison of pre-test and two post-tests ratings of the EI group, evaluated via an adapted version of the Vocabulary Knowledge Scale (Paribakht & Wesche, 1997), a discontinuous scale charting shifts in knowledge quality, revealed significant gains in the meanings of cognates and their use in sentences. The RC group did not outperform the Control group; instead, both the RC and Control groups displayed gains in cognate meaning but without concomitant improvement in using cognates in sentences. These findings are interpreted in light of: (i) phonological and script differences (Cyrillic versus Latin) that potentially camouflage inter-lexical connections; (ii) views positing the automaticity of cognate recognition; (iii) the value of repeated encounters with orthographic forms of cognates in the L2 script, even if decontextualized; (iv) favourable test effects in lexical acquisition; and (v) pedagogical practices in Ukrainian universities.

Abstract DDT01-02: Unleashing anti-tumor immunity through anti-OX40 monotherapy and in combination with anti-PD-L1

Abstract Cancer immunotherapy has the potential to induce durable responses through the generation of tumor-specific T cell memory. In addition to cognate antigen recognition, T cells require costimulation via stimulatory receptors for optimal memory T cell development and the establishment of anti-tumor immunity. OX40 is a costimulatory molecule that is expressed on activated effector and regulatory T cells. Agonistic antibodies against OX40 are predicted to counteract the immunosuppressive tumor microenvironment and promote T cell-dependent, anti-tumor immunity via two mechanisms: (1) binding to OX40 on antigen-experienced effector T cells increases their proliferation and cytokine production and (2) binding to OX40 on activated regulatory T cell inhibits their suppressive function, which in turn enhances the T cell based immune response. MOXR0916 is a humanized monoclonal antibody that binds to the human OX40 costimulatory receptor in an agonistic fashion. Binding of MOXR0916 to OX40 on activated human T cells in vitro resulted in the costimulation of effector T cell proliferation and IFN-g production, whereas binding to regulatory T cells inhibited their suppressive function. Due to sequence divergence between human and mouse OX40, a murine agonist antibody was employed to assess anti-tumor efficacy and T cell dynamics in murine syngeneic tumor models. In preclinical tumor models, anti-mouse OX40 administration induced a spectrum of anti-tumor activity, including durable responses. Animals with a complete response to anti-OX40 treatment were resistant to tumor rechallenge, indicating generation of tumor-specific memory. Tumor regression in anti-OX40 sensitive tumor models was associated with increased intratumoral expression of IFN-g, granzymes, and perforin at baseline, suggesting that anti-OX40 treatment augments latent immune responses to the tumor. Administration of anti-OX40 in several tumor models results in an increase in intratumoral CD8+ T cells and a decrease in regulatory T cells. Both anti-tumor efficacy and pharmacodynamic modulation of effector and regulatory T cells required antibody crosslinking. Similarly, anti-human OX40 MOXR0916 required antibody crosslinking to costimulate effector T cells. Treatment of agonistic anti-OX40 antibodies was capable of enhancing tumor immunity despite the activity of multiple inhibitory pathways including the PD-1- PD-L1 axis. In preclinical tumor models, the combination of anti-OX40 and a blocking antibody to the inhibitory receptor PD-L1 led to increased tumor growth inhibition and increased number of complete responses compared to either agent alone. This combination activity was associated with an increase in the expression of IFN-g associated genes and activated CD8+ T cells in the tumor. Together, these studies demonstrate that anti-OX40, both as a single agent and in combination with anti-PD-L1 can induce robust immune responses in animal tumor models. Citation Format: Jeong M. Kim. Unleashing anti-tumor immunity through anti-OX40 monotherapy and in combination with anti-PD-L1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr DDT01-02. doi:10.1158/1538-7445.AM2015-DDT01-02

Local antigen and inflammation in the lung induce the preferential establishment and maintenance of CXCR6 and CD49a-expressing antigen-specific CD8 TRM cells in the lung parenchyma and airways (MUC1P.900)

Abstract Acting as sentinels capable of quickly organizing a secondary immune response upon pathogen challenge, resident memory CD8 T (TRM) populations are initially primed by microenvironment cues and APC licensing following acute infection of peripheral tissues. Despite their capacity for heterologous protection against influenza virus (flu) challenge, scant knowledge exists as to factors necessary to establish and maintain airway and lung parenchymal (LP) CD8 TRM cells. In contrast to mechanisms described for other tissues, lung CD8 TRM cell establishment required cognate antigen recognition once cells were recruited to the lung by local inflammation. Furthermore, this combination of local antigen and inflammation formed long-lasting TRM populations in the LP and airways that highly express the chemokine receptor CXCR6 and adhesion molecule CD49a. During a primary intranasal (IN) flu infection, CXCR6 is preferentially expressed on virus-specific CD8 T cells in the airways and LP by day 7 post-infection. Selectively, LP CD8 TRM cells highly express CXCR6, while systemically circulating flu-specific cells achieve only an intermediate expression level. Finally, use of mixed bone marrow chimeras show that wild-type virus-specific memory CD8 T cells predominate over CXCR6-/- cells in the airway and LP after IN infection with Sendai or flu virus. Thus, our data show that local antigen and inflammation coupled with CXCR6 expression is key to establish CD8 TRM cells in the LP and airways.

The Molecular Landscape of Antibody-Mediated Kidney Transplant Rejection: Evidence for NK Involvement Through CD16a Fc Receptors

The recent recognition that antibody-mediated rejection (ABMR) is the major cause of kidney transplant loss creates strong interest in its pathogenesis. We used microarray analysis of kidney transplant biopsies to identify the changes in pure ABMR. We found that the ABMR transcript changes in the initial Discovery Set were strongly conserved in a subsequent Validation Set. In the Combined Set of 703 biopsies, 2603 transcripts were significantly changed (FDR < 0.05) in ABMR versus all other biopsies. In cultured cells, the transcripts strongly associated with ABMR were expressed in endothelial cells, e.g. cadherins CDH5 and CDH13; IFNG-treated endothelial cells, e.g. phospholipase PLA1A and chemokine CXCL11; or NK cells, e.g. cytotoxicity molecules granulysin (GNLY) and FGFBP2. Other ABMR transcripts were expressed in normal kidney but not cell lines, either increased e.g. Duffy chemokine receptor (DARC) or decreased e.g. sclerostin (SOST). Pathway analysis of ABMR transcripts identified angiogenesis, with roles for angiopoietin and vascular endothelial growth factors; leukocyte-endothelial interactions; and NK signaling, including evidence for CD16a Fc receptor signaling elements shared with T cells. These data support a model of ABMR involving injury-repair in the microcirculation induced by cognate recognition involving antibody and CD16a, triggering IFNG release and antibody-dependent NK cell-mediated cytotoxicity.

Necrotrophic effector epistasis in the Pyrenophora tritici-repentis-wheat interaction.

Pyrenophora tritici-repentis, the causal agent of tan spot disease of wheat, mediates disease by the production of host-selective toxins (HST). The known toxins are recognized in an ‘inverse’ gene-for-gene manner, where each is perceived by the product of a unique locus in the host and recognition leads to disease susceptibility. Given the importance of HSTs in disease development, we would predict that the loss of any of these major pathogenicity factors would result in reduced virulence and disease development. However, after either deletion of the gene encoding the HST ToxA or, reciprocally, heterologous expression of ToxA in a race that does not normally produce the toxin followed by inoculation of ToxA-sensitive and insensitive wheat cultivars, we demonstrate that ToxA symptom development can be epistatic to other HST-induced symptoms. ToxA epistasis on certain ToxA-sensitive wheat cultivars leads to genotype-specific increases in total leaf area affected by disease. These data indicate a complex interplay between host responses to HSTs in some genotypes and underscore the challenge of identifying additional HSTs whose activity may be masked by other toxins. Also, through mycelial staining, we acquire preliminary evidence that ToxA may provide additional benefits to fungal growth in planta in the absence of its cognate recognition partner in the host.

The ATP-mediated formation of the YgjD-YeaZ-YjeE complex is required for the biosynthesis of tRNA t6A in Escherichia coli.

The essential and universal N6-threonylcarbamoyladenosine (t6A) modification at position 37 of ANN-decoding tRNAs plays a pivotal role in translational fidelity through enhancement of the cognate codon recognition and stabilization of the codon–anticodon interaction. In Escherichia coli, the YgjD (TsaD), YeaZ (TsaB), YjeE (TsaE) and YrdC (TsaC) proteins are necessary and sufficient for the in vitro biosynthesis of t6A, using tRNA, ATP, L-threonine and bicarbonate as substrates. YrdC synthesizes the short-lived L-threonylcarbamoyladenylate (TCA), and YgjD, YeaZ and YjeE cooperate to transfer the L-threonylcarbamoyl-moiety from TCA onto adenosine at position 37 of substrate tRNA. We determined the crystal structure of the heterodimer YgjD–YeaZ at 2.3 Å, revealing the presence of an unexpected molecule of ADP bound at an atypical site situated at the YgjD–YeaZ interface. We further showed that the ATPase activity of YjeE is strongly activated by the YgjD–YeaZ heterodimer. We established by binding experiments and SAXS data analysis that YgjD–YeaZ and YjeE form a compact ternary complex only in presence of ATP. The formation of the ternary YgjD–YeaZ–YjeE complex is required for the in vitro biosynthesis of t6A but not its ATPase activity.

In Arabidopsis thaliana two co-adapted cyto-nuclear systems correlate with distinct ccmC transcript sizes.

Plant mitochondrial transcripts undergo maturation processes at both termini. Although frequently observed, the post-transcriptional formation of mature 5' ends is still poorly understood. We now analyzed the processing of transcripts derived from the mitochondrial ccmC gene, coding for a component of the cytochrome c maturation system. In Arabidopsis thaliana (Arabidopsis) there are two mitochondrial ccmC configurations, discriminated by a 66-bp sequence segment located approximately 500bp upstream of the ccmC gene. In Arabidopsis accessions these divergent mitochondrial genotypes correlate with the generation of two different 5' termini that map to positions around -484 in accession Columbia (Col ccmC genotype) or -390 in accession C24 relative to the translation start codon (C24 ccmC genotype). Previously we identified RNA PROCESSING FACTOR 3 (RPF3), a pentatricopeptide repeat (PPR) protein required for the maturation of ccmCmRNAs with -484 5' ends transcribed from the Col ccmC genotype. Now we identified several accessions defective in maturation of ccmC transcripts. Taking advantage of this natural genetic variation we identified RNA PROCESSING FACTOR 6 (RPF6), a PPR protein necessary for the generation of ccmCmRNAs with -390 5' ends transcribed from the C24 ccmC genotype. Both Col-type and C24-type accessions encode RPF3 and RPF6 so that they can process ccmC transcripts derived from the two different mitochondrial genotypes. These factors and their cognate RNA recognition sites in the different ccmC genotypes are an intriguing example for the evolution of two co-adapted cyto-nuclear systems required for the same process i.e. 5' maturation of ccmC transcripts.

Ribosome-induced tuning of GTP hydrolysis by a translational GTPase.

GTP hydrolysis by elongation factor Tu (EF-Tu), a translational GTPase that delivers aminoacyl-tRNAs to the ribosome, plays a crucial role in decoding and translational fidelity. The basic reaction mechanism and the way the ribosome contributes to catalysis are a matter of debate. Here we use mutational analysis in combination with measurements of rate/pH profiles, kinetic solvent isotope effects, and ion dependence of GTP hydrolysis by EF-Tu off and on the ribosome to dissect the reaction mechanism. Our data suggest that--contrary to current models--the reaction in free EF-Tu follows a pathway that does not involve the critical residue H84 in the switch II region. Binding to the ribosome without a cognate codon in the A site has little effect on the GTPase mechanism. In contrast, upon cognate codon recognition, the ribosome induces a rearrangement of EF-Tu that renders GTP hydrolysis sensitive to mutations of Asp21 and His84 and insensitive to K(+) ions. We suggest that Asp21 and His84 provide a network of interactions that stabilize the positions of the γ-phosphate and the nucleophilic water, respectively, and thus play an indirect catalytic role in the GTPase mechanism on the ribosome.

HIV-1 Intersection with CD4 T Cell Vesicle Exocytosis: Intercellular Communication Goes Viral.

In cells of the immune system, the secretion of extracellular vesicles is modulated through cellular activation. In particular, T cell activation is achieved through cell–cell contacts with antigen presenting cells and the consequent formation of a specialized signaling junction called the immunological synapse. Recent works on CD4 T cells have elucidated that cognate antigen recognition by the T cell receptor (TCR) engages two distinct exocytic events. The first involves the exocytic targeting of signaling molecules at the synaptic membrane and drives the functional architecture of the immunological synapse. The second enlists the extracellular secretion of the TCR itself, once the functional architecture of the immunological synapse is accomplished. HIV-1, a human lymphotropic virus, has evolved sophisticated mechanisms to co-opt CD4 T cell physiology. Notably, it has become apparent that HIV-1 intersects the regulated secretory system of CD4 T cells in order to bud from the plasma membrane of the infected cell and to promote bystander cell death. Here, I review the relevance of CD4 vesicle exocytosis to immune regulation and to HIV-1 pathogenesis and discuss their potential therapeutic applications.

Molecular Events in Human T Cell-Mediated Rejection: The Relationship Between Innate Immunity and Cognate Recognition.

Molecular Events in Human T Cell-Mediated Rejection: The Relationship Between Innate Immunity and Cognate Recognition.

Erratum to: Phylogeographic evidence of cognate recognition site patterns and transformation efficiency differences in H. pylori: theory of strain dominance

Erratum to: Phylogeographic evidence of cognate recognition site patterns and transformation efficiency differences in H. pylori: theory of strain dominance

LFA-1 and CD62L dependent transient surface CCR5 expression in naïve CD8+ T cells enhances T cell immune memory (CCR3P.214)

Abstract The initiation of an effective adaptive immune response requires choreographed interaction among rare antigen-bearing dendritic cells (DCs) with antigen-specific CD4+ and CD8+ T cells in the lymph node (LN). This interaction is especially critical for the magnitude of memory T cell generation. We and others have previously demonstrated that CCL3/CCL4 secretion from productive interaction between antigen-specific T cell and antigen-bearing DCs promote local recruitment of naïve CD8+ T cells in the inflamed LNs, implying that naïve CD8+ T cells can express CCR5 in the inflamed LN microenvironment. Here, we examined the kinetics of CCR5 expression on naïve T cells upon entering an inflamed LN. Maximum surface CCR5 expression occurs in 10-30% of newly arrived naive T cells within the first 6 hours via mobilization of pre-existing CCR5 protein found in intracellular vesicles, and this transient up-regulation of surface CCR5 expression in CD8+ T cells was dependent on direct physical contact with LFA and CD62L, as ligation of CD8+ T cells with anti-CD11a and/or anti-CD62L antibodies enhances surface CCR5 expression within 1 hour in the absence of TCR stimulation. More importantly, CCR5+ fraction of naïve CD8+ T cells exhibit enhanced ability to become memory T cells. Our study implicates an important functional role for CCR5 expression by naïve lymphocytes prior to cognate antigen recognition for enhanced memory T cell development.

Cycling Memory CD4+T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

The mechanisms of increased memory CD4+ T cell cycling in HIV disease are incompletely understood but have been linked to antigen stimulation, homeostatic signals, or exposure to microbial products and the inflammatory cytokines that they induce. We examined the phenotype and Vβ family distribution in cycling memory CD4+ T cells among 52 healthy and 59 HIV-positive (HIV+) donors. Cycling memory CD4+ T cells were proportionally more frequent in subjects with HIV infection than in controls, more often expressed CD38 and PD-1, and less frequently expressed OX40 and intracellular CD40L. OX40 expression on memory CD4+ T cells was induced in vitro by anti-CD3, interleukin-2 (IL-2), IL-7, or IL-15 but not by Toll-like receptor ligands. In HIV+ donors, memory CD4+ T cell cycling was directly related to plasma lipopolysaccharide (LPS) levels, to plasma HIV RNA levels, and to memory CD8+ T cell cycling and was inversely related to peripheral blood CD4+ T cell counts but not to the levels of IL-2, IL-7, or IL-15, while in HIV-negative donors, memory CD4+ T cell cycling was related to IL-7 levels and negatively related to the plasma levels of LPS. In both controls and HIV+ donors, cycling memory CD4+ T cells had a broad distribution of Vβ families comparable to that of noncycling cells. Increased memory CD4+ T cell cycling in HIV disease is reflective of generalized immune activation and not driven primarily by cognate peptide stimulation or exposure to common gamma-chain cytokines. This cycling may be a consequence of exposure to microbial products, to plasma viremia, or, otherwise, to proinflammatory cytokines. This work provides evidence that the increased memory CD4+ T cell cycling in HIV infection is not a result of cognate peptide recognition but, rather, is more likely related to the inflammatory environment of HIV infection.

Mechanisms of innate lymphoid cell and natural killer T cell activation during mucosal inflammation.

Mucosal surfaces in the airways and the gastrointestinal tract are critical for the interactions of the host with its environment. Due to their abundance at mucosal tissue sites and their powerful immunomodulatory capacities, the role of innate lymphoid cells (ILCs) and natural killer T (NKT) cells in the maintenance of mucosal tolerance has recently moved into the focus of attention. While NKT cells as well as ILCs utilize distinct transcription factors for their development and lineage diversification, both cell populations can be further divided into three polarized subpopulations reflecting the distinction into Th1, Th2, and Th17 cells in the adaptive immune system. While bystander activation through cytokines mediates the induction of ILC and NKT cell responses, NKT cells become activated also through the engagement of their canonical T cell receptors (TCRs) by (glyco)lipid antigens (cognate recognition) presented by the atypical MHC I like molecule CD1d on antigen presenting cells (APCs). As both innate lymphocyte populations influence inflammatory responses due to the explosive release of copious amounts of different cytokines, they might represent interesting targets for clinical intervention. Thus, we will provide an outlook on pathways that might be interesting to evaluate in this context.

Phylogeographic evidence of cognate recognition site patterns and transformation efficiency differences in H. pylori: theory of strain dominance

BackgroundHelicobacter pylori has diverged in parallel to its human host, leading to distinct phylogeographic populations. Recent evidence suggests that in the current human mixing in Latin America, European H. pylori (hpEurope) are increasingly dominant at the expense of Amerindian haplotypes (hspAmerind). This phenomenon might occur via DNA recombination, modulated by restriction-modification systems (RMS), in which differences in cognate recognition sites (CRS) and in active methylases will determine direction and frequency of gene flow. We hypothesized that genomes from hspAmerind strains that evolved from a small founder population have lost CRS for RMS and active methylases, promoting hpEurope’s DNA invasion. We determined the observed and expected frequencies of CRS for RMS in DNA from 7 H. pylori whole genomes and 110 multilocus sequences. We also measured the number of active methylases by resistance to in vitro digestion by 16 restriction enzymes of genomic DNA from 9 hpEurope and 9 hspAmerind strains, and determined the direction of DNA uptake in co-culture experiments of hspAmerind and hpEurope strains.ResultsMost of the CRS were underrepresented with consistency between whole genomes and multilocus sequences. Although neither the frequency of CRS nor the number of active methylases differ among the bacterial populations (average 8.6 ± 2.6), hspAmerind strains had a restriction profile distinct from that in hpEurope strains, with 15 recognition sites accounting for the differences. Amerindians strains also exhibited higher transformation rates than European strains, and were more susceptible to be subverted by larger DNA hpEurope-fragments than vice versa.ConclusionsThe geographical variation in the pattern of CRS provides evidence for ancestral differences in RMS representation and function, and the transformation findings support the hypothesis of Europeanization of the Amerindian strains in Latin America via DNA recombination.

Inhibition of TGF-β1 signaling promotes central memory T cell differentiation.

This study affirmed that isolated CD8(+) T cells express mRNA and produce TGF-β following cognate peptide recognition. Blockage of endogenous TGF-β with either a TGF-β-blocking Ab or a small molecule inhibitor of TGF-βRI enhances the generation of CD62L(high)/CD44(high) central memory CD8(+) T cells accompanied with a robust recall response. Interestingly, the augmentation within the central memory T cell pool occurs in lieu of cellular proliferation or activation, but with the expected increase in the ratio of the Eomesoderm/T-bet transcriptional factors. Yet, the signal transduction pathway(s) seems to be noncanonical, independent of SMAD or mammalian target of rapamycin signaling. Enhancement of central memory generation by TGF-β blockade is also confirmed in human PBMCs. The findings underscore the role(s) that autocrine TGF-β plays in T cell homeostasis and, in particular, the balance of effector/memory and central/memory T cells. These results may provide a rationale to targeting TGF-β signaling to enhance Ag-specific CD8(+) T cell memory against a lethal infection or cancer.

Factoren bij het herkennen van cognaten in onbekende talen: algemeen of taalspecifiek?

The correct recognition of cognate relationships is a precondition for receptive multilingualism within language families. Several item- and participant-related factors have been identified that affect the probability with which readers and listeners correctly recognise and translate cognates in an unknown but genealogically related foreign language. Most of the relevant findings, however, are based on tasks featuring cognates in only one unknown language, leaving open the possibility that these factors play a (somewhat) different role depending on the specific stimulus language. To address this issue, 98 German-speaking participants were asked to translate 181 written cognates from four Germanic languages (Danish, Dutch, Frisian and Swedish). The effects of stimulus similarity to known (L1, L2, …, Ln) cognates, cognate frequency and the participants’ foreign language skills on translation accuracy were assessed and found not to vary substantially between stimulus languages. This indicates that the validity of studies on cognate recognition extends beyond the language from which the stimuli were sampled. Secondary findings are discussed as well.