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Given the key role 4-1BB plays in the stimulation of T cells, humanization of agonistic anti-human 4-1BB monoclonal antibody (mAb) may have important clinical applications. In this paper, we present the humanization of agonistic anti-human 4-1BB mAb, BBK-4, using a phage display library. We first prepared the combinatorial library by incorporating murine and human alternative at positions representing buried residues that might affect the structural integrity of the antigen binding site. Six humanized single chain Fv (scFv) fragments were selected from the combinatorial library expressing phage-displayed humanized scFv. They were found to retain the epitope specificity of the original mAb but had affinities of lower than 1/10 of the original. In spite of the lower affinity, the humanized scFv coated on the surface expanded human peripheral blood mononuclear cells (PBMCs) in MLR similarly to the original mAb in the presence of anti-CD3 mAb. These results suggest that humanized anti-human 4-1BB scFvs can be used as a valuable reagent for clinical application. [Copyright &y& Elsevier]

T-cells provide antigen specific focus to the adaptive immune response. However, the receptors that initiate functional responses are not in themselves specific, as they can recognise many different ligands. In this paper, we propose that the immune system deals with TCR degeneracy by an adaptive process that effects both T-cell activation and T-cell function, and exploits TCR degeneracy to limit pathogenic autoimmune disease. [Copyright &y& Elsevier]

This paper discusses some consequences of the discovery that antigen receptors are degenerate: Immune specificity, in contrast to the tenets of the clonal selection paradigm, must be generated by the immune response down-stream of initial antigen recognition; and specificity is a property of a collective of cells and not of single clones. [Copyright &y& Elsevier]

Age-related immunological dysfunctions of T cells, B cells, and antigen-presenting cells (APCs) have been demonstrated in normal mice and SAM. To elucidate the causes of various age-associated diseases and restore impaired immunological functions, we carried out bone marrow transplantation (BMT) with or without thymus grafts from normal mice to SAM, and found the following: (i) Conventional BMT can be used to prevent the development of accelerated presbycusis in SAMP1 mice; (ii) Intra-bone marrow (IBM)-BMT (injection of bone marrow cells into the bone marrow cavity) can be used to not only prevent but also treat osteoporosis in SAMP6 mice, since both hemopoietic stem cells and mesenchymal stem cells are replaced by normal donor cells after IBM-BMT; and (iii) Conventional BMT plus thymus grafts can be used to prevent the development of amyloidosis in SAMP1 mice. In this paper, we discuss whether age-associated diseases are “stem cell disorders” (hemopoietic stem cell disorders and mesenchymal stem cell disorders). [Copyright &y& Elsevier]

Although mechanisms operative in the induction and maintenance of specific, adaptive immunity, including ‘cognate’ B/T interactions, have been extensively studied and defined, we still know little about the mechanisms operative in developing and maintaining B- and T-cell dependent ‘natural’ immunity. Particularly, we are still rather ignorant concerning gut microbial/gut or systemic APC, T cell and B cell interactions that lead to lymphoid cell mediated ‘natural’ immunity: specific or broadly reactive, activation via TCR and BCR and/or via other receptors such as the TLR series, and whether T/B interactions are operative at this level? Here we will address: (1) the general role of gut microbes in the development and maintenance of the intestinal, humoral immune system; (2) the general role of gut microbes in the development of B1 cell mediated, ‘natural’ gut IgA and the dependence of these B1 cells on bystander T cell help; (3) the relative contributions of B1 versus B2 cells to gut ‘natural’ and specific IgA responses; (4) the role for particular ‘normal’ gut microbes in the initiation of inflammatory bowel diseases (IBD) in mice with a dysregulated immune system; and (5) the possible roles of gut microbes in facilitating oral tolerance, a mechanism likely operative in forestalling or ameliorating IBD. A central theme of this paper is to attempt to define the specificities of activated, functional CD4+ T cells in the gut for Ags of particular, usually benign gut microbes. We will also consider the still-unresolved issue of whether the contributions of B1-derived IgA in the gut to the ‘natural’ Ab pool are Ag-selected and driven to proliferation/differentiation or whether the main stimuli are not via BCRs but rather other receptors (TLRs, etc.). The main experimental approach has been to use antigen-free, germ-free, or gnotobiotic (mono- or oligo-associated with precisely known bacterial species) mice. [Copyright &y& Elsevier]

A major challenge for immunologists has been the development of vaccines designed to emphasize cellular immune responses. One particularly promising approach is the prime–boost strategy, which has been shown to generate high levels of T-cell memory in animal models. Recently, several papers have highlighted the power of prime–boost strategies in eliciting protective cellular immunity to a variety of pathogens and have demonstrated efficacy in humans. Coupled with recent advances in our understanding of the mechanisms underlying the generation, maintenance and recall of T-cell memory, the field is poised to make tremendous progress. This Review discusses the impact of these recent developments on the future of prime–boost vaccine strategies. [Copyright &y& Elsevier]

Immunobiologics provide the hope for safe and effective long-term management of psoriasis, a life-disabling condition. The use of targeted immunotherapies as pathogenic probes has led to scientific discoveries that help uncover new information on the pathogenesis of psoriasis and on the control of cutaneous immunity. The research described in this paper employs targeted immunotherapies as pathogenic probes of T1-mediated immune disorders, using psoriasis as the primary disease model. This approach has wide applicability to other immune-mediated inflammatory isorders. [ABSTRACT FROM AUTHOR]

CCL27 (also named CTACK, ALP, ILC and ESkine) is a CC chemokine primarily expressed by keratinocytes of the skin. The cognate receptor of CCL27 named CCR10 (GPR-2), is also expressed in skin-derived cells, and in addition by a subset of peripheral blood T-cells and in a variety of other tissues. In this paper, we report the cloning of porcine CCL27 cDNA and investigation of CCL27 mRNA expression in Staphylococcus hyicus infected piglets. At the protein level, 77 and 74% homology was found to human and mouse CCL27 sequences, respectively. The results of the expression analyses show that CCL27 mRNA is upregulated in the skin of infected piglets and to a lesser extent in piglets recovered from disease and without clinical signs of infection, indicating a role for CCL27 both during inflammation and after recovery from an infection. [Copyright &y& Elsevier]

Summary: Th2 cells play a central role in type I allergies. However, the source of interleukin-4 which may lead to a Th1/Th2 imbalance is unknown. Vα24+CD161+ Natural killer T (NKT) cells secrete high amounts of interleukin-4 and/or interferon-γ and are assumed to participate in the initiation of Th1/Th2 immune responses. Their contribution to the development of Th2-dependent type I allergies is controversial.Our objective in this paper was to determine whether Vα24+CD161+ NKT cells differ in atopic and non-atopic adults.Venous blood was obtained from thirteen atopic and sixteen healthy adult probands. Vα24+CD161+ NKT cells were determined in CD4+, CD8bright/dim and CD4−CD8− lymphocytes by flow cytometry. At the molecular level, the amounts of T cell receptor (TCR) AV24-AJ18 transcripts were quantified with respect to TCRAV24 chain transcripts alone or to all TCR alpha chain transcripts. To detect potential inserted nucleotides in the N-region, a novel real-time PCR-based technology was applied.Both CD4+ and CD4−CD8− NKT cells were present at higher frequencies than CD8+ NKT cells in all probands. CD8dim NKT cell levels were lower in healthy individuals, although not statistically significantly different to the patients. Amounts of AV24-AJ18 transcripts in relation to total TCR alpha-chains and to TCRAV24 alone were equal in both proband groups. N-region diversity was detected in four clones from four different individuals, but altered the amino acid sequence in only one clone of an atopic donor.Analysis of Vα24+CD161+ NKT cell frequencies at both the cellular and molecular levels failed to reveal significant differences in peripheral blood of atopic and non-atopic probands. If NKT cells contribute to development of type I allergies they must do so at earlier times or in other locations. [Copyright &y& Elsevier]

Relative avidities of antigen-specific T cells for major histocompatibility complex peptide complexes (MHCp) have recently been measured by MHC tetramer dissociation assays, but there is no consensus on the methodologies used for these experiments. While we do not question the conclusions reached in previous studies, in this paper we discuss the caveats that are present in the design of all MHCp tetramer dissociation protocols, and we propose a set of criteria that should be met in the evaluation of appropriate methodologies. We find that it is necessary to use specific reagents to compete with rebinding of the labeled tetramer, but that when either intact anti-MHC antibodies or cold MHC tetramers are used, the dissociation rates are dependent upon the concentrations of the competitor. In contrast, we demonstrate that apparent dissociation rates are independent of the competitor concentration when blocking anti-MHC Fab fragments are used, suggesting that these are the most appropriate reagents to use for tetramer dissociation experiments. [Copyright &y& Elsevier]

One of the mechanisms ensuring immunological unresponsiveness or tolerance depends on the action of CD8+ lymphocytes. In this paper, we report that, in healthy subjects, a subset of CD8+CD28− T cells suppresses the specific response to TSH receptor (TSHR) of CD4+ clones. Suppression was highly specific, required cell–cell interaction, and was not mediated by cytotoxicity. Co-incubation of CD8+ and CD4+ clones, followed by the removal of the CD8+ cells from the cultures before testing CD4+ responsiveness to TSHR, demonstrated that CD4+ cells were anergic since they showed low response to the antigen and a significant impairment of IL-2 production. In CD8-mediated anergy induction, the T-cell receptor (TCR) on both CD4+ and CD8+ cells seems to play a role. Our results indicate that one of the mechanisms ensuring peripheral tolerance involve CD8+CD28− cells. A disregulation in the control of autoreactive clones by this subset might be important for the onset of autoimmune thyroid diseases. [Copyright &y& Elsevier]

Immunology in recent years has taken a somewhat surprising turn, expressed by a renewed interest in innate immunity. Especially intriguing is the regulatory role exerted by the innate components on the adaptive response, with Toll receptors and complement components being the most investigated. This function has been firmly established for complement protein CR2 (CD21) as part of the BCR co-receptor CD19/CD21/CD81. New findings are now providing a broader picture of complement and its tuning of the immune response; for example, complement proteins have been implicated in the control of T-cell-mediated responses. We will review some of these data here and summarize new discoveries in areas of research on more traditional topics within the complement literature, such as complement and renal diseases, and the therapeutic use of C1-Inhibitor. We cover papers selected from studies presented at the XIX International Complement Workshop, held in Palermo in September 2002, and published within the past six months. [Copyright &y& Elsevier]

The TCL1 (T-cell leukemia 1) protooncogene is highly expressed in many human B-cell leukemias and two recent papers show that TCL1 overexpression causes rapid development of B-cell lymphomas in mice. Other recent work showing that the TCL1 protein enhances the activation of the pro-survival kinase Akt has revealed a potential mechanism underlying the development of B-cell leukemias and raised new questions about the regulation of Akt. [Copyright &y& Elsevier]

A physiologically structured population model of T cell populations at the end of an immune response is proposed and analysed. The proposed model describes a T cell population with a structured death rate mediated by cytokine receptor surface expression. This provides a structuring that determines the ability of a T cell to compete for survival cytokines. Homogeneous differentiation into memory combined with heterogeneous survival abilities leads to a system of nonlinear first-order integro differential equations. The mathematical model is studied analytically by a perturbation approach which agrees well with numerical integrations. We find that the structured death rate leads to selection of T cells expressing high cytokine receptor levels. Selection in this model is independent of the initial T cell distribution which allows us to define a universal selection curve, a property lost under receptor downregulation (i.e. loss of cytokine receptors from the surface). Furthermore, we examine the effects of a population dependent memory differentiation rate and of cytokine receptor downregulation on selection. A population dependent memory differentiation rate increases selection significantly while putting an upper bound on the number of T cells differentiating into memory. Under receptor downregulation a dramatic change of the memory T cell distribution is induced. We find that there exists a critical ratio of the receptor downregulation rate to the average T cell death rate for which selection becomes maximal. Our analysis reveals that this maximum property is the result of an interplay between single cell dynamics and population dynamics. We propose that the selection studied in this paper plays an important role in the selection of optimal T cells for the memory pool. [Copyright &y& Elsevier]

Combinatorial libraries and in particular positional scanning synthetic combinatorial libraries (PS-SCL) allow the study of T cell specificity. This is a systematic and unbiased approach that does not require any previous knowledge about the clones to be studied, neither their specificity nor they major histocompatibility complex (MHC) restriction. Two different types of T cell clone ligands can be identified: (1) peptides that do not necessarily correspond to proteins described in the databases, and (2) peptides that are fragments of natural proteins. In this paper, relevant examples of the application of PS-SCL and the deconvolution strategies followed to identify T cell epitopes for clones of known and unknown specificity will be reviewed. Also, important issues like the immunogenicity of such T cell ligands will be discussed. [Copyright &y& Elsevier]

Structurally well-defined immune stimulatory molecules are important components of new generation molecular vaccines. In this paper, the design and synthesis of two lipid A analogues containing an unnatural tri-lipid acyl group are described. In a totally synthetic liposomal vaccine system, these re-designed lipid A analogues demonstrate potent immune stimulatory properties including antigen specific T-cell activation. [Copyright &y& Elsevier]

Most mammalian immune systems and parasites have co-evolved over the millennia, interacting within a common environment and communicating through a common language. This language is comprised of copious dialects in which a variety of host innate and acquired immune pathways actively interact with a multitude of parasite-specific survival strategies. Nonetheless, a simplified language is likely present since the same basic molecular and cellular mechanisms are associated with resistance or susceptibility to parasite infection. Protective immunity against protozoa within the phylum Apicomplexa (e.g. Cryptosporidia, Eimeria, Neospora, Plasmodia and Toxoplasma) is generally CD4+ T cell-dependent and elicited along the IL-12/IFN-γ/iNOS effector axis. This simplified language can be decoded in part by significant advances in understanding naı¨ve T cell activation, differentiation and generation of immunologic memory. Vaccine adjuvants and new immunisation strategies for generation of more potent immunity can also be viewed through this common language lens. The aim of this paper is to summarise recently published fundamental immunology studies, their relevance through examples in specific coccidian-host immune dialects, and how this simplified language can be used for the more rationale design of parasite vaccine control strategies. [Copyright &y& Elsevier]

Dendritic cells (DCs) are recognized as the sole professional antigen-presenting cells capable of priming naive T cells of the helper and cytotoxic phenotypes. This property is presently exploited with success in vaccinal strategies against pathogens or tumor cells that otherwise escape immune recognition, but the repeated infusions of ex vivo expanded and sensitized DCs are usually required to achieve protection. In this paper, we demonstrate that liposomal antigens can efficiently relay and propagate the action of DCs, inducing a strong long-term response against their associated antigen. Their effect is mainly achieved by improving the ex vivo loading of DCs and by efficiently channeling the activation stimulus into the induction of effector function. This is demonstrated by the sustained immunoglobulin production as well as by the sustained lymphoproliferation and the increased cytokine secretion that can be achieved upon restimulation of DC-primed immune cells with limited amount of liposomal antigenic material. Being well-tolerated and easily prepared, liposomal antigens could therefore be expected to significantly contribute to the efficiency and to a more general utilization of the highly promising but rather cumbersome DC-based immunotherapies. [ABSTRACT FROM AUTHOR]

γδ T lymphocytes are considered to represent a link between the inflammatory response and adaptive immunity. In the present paper we investigated whether these cells play any role in the remodeling of the immune system described in the elderly. We show that the absolute number of γδ T cells in peripheral blood of old and very old subjects is reduced. Moreover, γδ T cells from old people and centenarians show enhanced levels of the early activation marker CD69 both after culture in medium alone and in LPS-stimulated cells. Furthermore, they show a basal increased production of tumor necrosis factor (TNF)-α as evaluated at the single cell level. Additionally, the response of these cells to IPP in ‘in vitro’ cultures is in part impaired. These results suggest that the high level of basal activation of γδ T cells is due to the ‘inflamed’ environment. However, the changes in number and function of γδ T lymphocytes might influence the resolution of inflammatory immune responses in the elderly. [Copyright &y& Elsevier]

Objective It has been suggested that the development of uterine leiomyomas is positively influenced by an immune system in a chronically inflammatory state and that a lower level of regulating T cell (Treg cells) would play a central role. Since it has been suggested that the W620 variant of protein tyrosine phosphatase non-receptor type 22 (PTPN22) decreases the number of Treg cells, we investigated a possible relationship between PTPN22 polymorphism and uterine leiomyomas. Study design We studied 203 white women from Rome who were hospitalized for symptomatic leiomyomas requiring surgical intervention. These women were considered in a previous paper regarding the relationship between ACP1 and dimension of leiomyomas. As controls we studied 355 healthy women from the same population with comparable age and without clinical evidence of leiomyomas. All women gave written informed consent to participate to the study. Chi square test of independence and T -test for difference between means were performed by SPSS package. Results Considering the whole sample, a borderline association between PTPN22 and leiomyomas was observed: the *C/*T genotype is more frequent in cases than in controls. This association is marked and statistically significant in younger women only. The main diameter of tumor is significantly greater in *C/*T than in *C/*C women. This effect is present in younger women only. The *C/*T genotype also shows a higher tendency to intramural localization, but no effect of age is observed upon this association. Conclusions The data suggest a positive effect of *C/*T genotype on susceptibility to leiomyomas in younger women. In these women a *C/*T genotype favors the growth of leiomyomas. [ABSTRACT FROM AUTHOR]

The mechanisms through which tumor antigen-specific T cells are elicited in natural or chemotherapy-induced immunosurveillance have been elusive. In this issue of Cancer Cell , two papers by Broz and colleagues and Ruffell and colleagues delineate an important role for a specific dendritic cell subset characterized by CD103 expression, dependence on transcription factors Batf3 and Irf8, and interleukin-12 production. [ABSTRACT FROM AUTHOR]

CD8+ memory T cells are critical for immunity against intracellular pathogens. Epidemiological evidence demonstrates that bystander infection can impact immune responses to co-infection or vaccination. A recent paper in Immunity demonstrates that persistent bystander inflammation can negatively impact CD8+ T cell effector to memory transition and protection from subsequent infection. [ABSTRACT FROM AUTHOR]

Interaction of T lymphocytes with other cell types is important for normal T-cell development and function. Recently, a number of adhesion molecules important in T-cell interactions with other cell types have been defined. In this paper we review the role of two adhesion pathways, CD2/LFA-3 and LFA-1/ICAM-1, in T-cell interactions with epithelial cells of the thymus and skin. While thymic epithelium-T-cell interactions were mediated by both the LFA-1/ICAM-1 pathway and the CD2/LFA-3 pathway, epidermal-T-cell interactions were mediated primarily by the LFA-1/ICAM-1 pathway. Although ICAM-1 was not expressed in vivo on epidermal keratinocytes in normal skin, ICAM-1 was expressed by epidermal keratinocytes at the site of T-cell infiltration in inflammatory dermatitis. ICAM-1 was expressed in vivo on thymic epithelium. Both LFA-3 and ICAM-1 were expressed on epithelial cells of thymus and skin early on in fetal ontogeny. These antigen-independent adhesion molecules play an important role in the cell-cell interactions associated with T-cell differentiation and function. [ABSTRACT FROM AUTHOR]

HIV-1 persistence in long-lived cellular reservoirs remains a major barrier to a cure. In a recent Nature Medicine paper, Buzon et al. identify memory T cells with stem cell-like properties (TSCM) that harbor infectious provirus and that likely contribute to HIV-1 persistence. [ABSTRACT FROM AUTHOR]

• Inverted T helper (CD4)/Cytotoxic T cell (CD8) ratio in Boran cattle. • Higher absolute numbers of circulating CD8 T cells in Boran cattle than EASZ, N'dama, Nelore and Holstein-Friesian. • Female cattle have significantly higher CD4/CD8 ratio than male cattle. The CD4+/CD8+ ratio is used as a marker of the immune regulation of T cell balance. When the ratio in peripheral blood is less than 1, this is considered an indication of immune suppression in an individual. Previous work on bovine Peripheral Blood Mononuclear Cells (PBMC) has consistently reported a ratio ≥1 as seen in other mammalian hosts, i.e. higher circulating CD4+ cell numbers than CD8+ cell numbers. However, a consistent inverted CD4+/CD8+ ratio (<1) was observed in Boran cattle, an African Bos indicus breed. The T cell populations were characterized in Boran cattle (n = 52), revealing higher percentages of circulating CD8+ cells (31.9 % average) than CD4+ cells (19.1 % average), thus resulting in the inversion of the expected T cell homeostasis in these animals. The results show that this inversion is not an effect of age or relatedness of the cattle, rather, it was shared by almost all Boran cattle used in this study. Despite this inversion being a feature shared by both males and females, the female cattle had significantly higher CD4+/CD8+ ratios than the male Boran. This paper describes the characteristics of the T cell fractions in the study animals and compares the findings to those of other Boran cattle in Kenya, and four other cattle breeds representing African indicine, African taurine, Brazilian indicine and European taurine cattle. We demonstrate that the consistent observation of inverted CD4+/CD8+ cell ratio was restricted to the Boran. [ABSTRACT FROM AUTHOR]

Magnetic nanoparticle is an important branch of nanomaterials, especially magnetic iron oxide (Fe 3 O 4) nanoparticles have attracted widespread attention due to the fact that they can be used not only as high-sensitivity magnetic resonance contrast agents, but also as carriers for the construction of multifunctional and intelligent nanoprobes. The functional ligands modified on the surface of nanoprobes always provide the effective targeting ability. However, during the coupling process, the competitive inhibition of different modified ligands probably affects the construction of nanoprobes. Therefore, a modular designed method to construct magnetic nanoprobes is proposed in this paper and this method provides the favorable coupling efficiency and activity of the modified ligands as well as the inconspicuous competitive coupling effect between different ligands. The nanoprobes are composed of streptavidin modified Fe 3 O 4 nanoparticles and the biotinylated functional ligands assembled on the nanoparticles. Due to the specific binding between streptavidin and biotin, the functional ligands are coupled on the Fe 3 O 4 nanoparticles and the different ligands could be simply replaced to construct the nanoprobes with different function. Two types of dual-targeted nanoprobes including CD20&CD3@Fe 3 O 4 and E5&CD3@Fe 3 O 4 are synthesized. These nanoprobes have the appropriate hydrodynamic size (∼20 nm) and desirable magnetic properties (about 240 mM-1s-1 for r 2 relaxivity). In cell experiments, CD20&CD3@Fe 3 O 4 and E5&CD3@Fe 3 O 4 showed strong cytotoxicity for Raji cells and HL60 cells respectively and enhanced the T cell mediated immunotherapy which provided dual-targeted ability in vitro. [ABSTRACT FROM AUTHOR]

Abstract: In the past decade it has been established that regulatory T cells (Tregs) control all immune responses. As the induction and effector mechanisms used by Tregs are being unraveled, it is emerging that a reciprocal population of CD4+ T lymphocytes exists in the immune system that produces inflammatory cytokine IL-17, and coined "Th17 cells". Th17 cells have been implicated in the pathogenesis of many forms of human disease. The development, function, mechanism of action, and homeostasis of Tregs and Th17 cells, and the reciprocal control between Tregs and Th17 cells were presented at the Second International Conference on Regulatory T Cells and Th17 Cells and Clinical Application in Human Diseases in Shanghai on 17–20 July 2010 (China Tregs/Th17 2010). In this Special Issue of International Immunopharmacology, several paper submitted to the conference will highlight the biology of Tregs and Th17 cells, and their clinical application in human disease. [Copyright &y& Elsevier]

Abstract: A critical comment to our paper on Kv1.3 channels in the immunological synapse (IS) was published, which emphasized the role of two-pore potassium channels (TASK-1 and 3) in the physiology of T lymphocytes . Here we provide several lines of evidence that presence of TASK channels in the T cell line (a murine Th2 Cell line, D10) used in our experimental model cannot explain the changes in the biophysical parameters of the whole-cell current upon formation of an IS . [Copyright &y& Elsevier]

Abstract: Regulatory T cells (Tregs) are subsets of T cells that are specifically dedicated to controlling immune responses. It has been established that Tregs play a key role in regulating autoimmune disease, allergy, cancer, infectious disease, and in the induction of transplantation tolerance. The latest progress in the development, function, mechanism of action, and homeostasis of regulatory T cells, and their translation to the clinic were presented at the International Conference on Regulatory T Cells and Clinical Application in Human Diseases in Beijing on 25–27 October 2008 (China Tregs 2008). In this Special Issue of International Immunopharmacology, several papers submitted to the China Tregs 2008 will highlight some of the recent advances in the biology of regulatory T cells and current strategies to translate regulatory T cells into the clinic. [Copyright &y& Elsevier]

The entry of exogenous antigen into the MHC class I-restricted crosspresentation pathway can contribute to CD8+ T cell tolerance and immunity, in particular to peripheral self-antigens or selected viruses and bacteria showing restricted tissue tropism. Dendritic cells are the key crosspresenting cells and, as such, they are thought to carry specialized machinery dedicated to this purpose. Two recent papers describe intracellular components tailored to the dendritic cell crosspresentation pathway. [Copyright &y& Elsevier]

A 30Gbps power-efficient equalizer including an adaptive loop combined with a direct current offset cancellation (DCOC) loop is presented in this paper. Based on spectrum balanced technique, the adaptive loop applies signal strength indication (SSI) circuit to detect the low and high frequency power of equalized signal. After that, peaking gain of equalizer is adjusted according to detection value of SSI circuits. With the help of operation amplifier and trans-conductance amplifier, the proposed DCOC loop decreases the mismatch error. By applying inductive peaking and RC-degeneration technique, the continuous time linear equalizer (CTLE) compensates for channel insert loss in equalizer. A double- f T cell with inductive peaking technique is utilized to expand the bandwidth. To reduce effect of parasitic capacitor from output buffer, equalized signal is reshaped by three-stage cascaded limiting amplifier. Benefiting from excellent impedance matching by employing micro-strip and peaking inductor in terminal, the maximum channel loss equalized at 14 ​GHz is −18dB. The maximum reflection loss of Sdd11 and Sdd22 measured at 42 ​GHz and below are -9dB. Peak-peak jitter of 11.33ps is measured at 30Gbps after equalization. Meanwhile, only 53 ​mW power dissipation is consumed with a power supply of 1.8 ​V. Fabricated in 0.13 ​ ​μm SiGe BiCMOS technology, this chip only occupies active area of 0.32 ​mm2. [ABSTRACT FROM AUTHOR]

Patients who fail to adequately reconstitute the donor-derived immune system after allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for infections and leukemia relapse. In the past, pan T-cell depleted haploidentical grafts were associated with delayed immune reconstitution (IR). Recently, the majority of patients receiving αβ T-cell/B-cell depleted haploidentical HSCT (αβhaplo-HSCT) reach a threshold of 200 CD3+ T cells/mcl by 100 days after HSCT (Bertaina A et al. Blood 2014 Jul 31;124(5):822-6). However, a proportion of patients experience a slower IR with consequent higher morbidity and mortality. Early prediction of delayed IR may permit prompt clinical intervention such as infusion of donor lymphocytes or of virus-specific cytotoxic T cells. Flow cytometry, the most widely applied approach for IR analysis, suffers from intrinsic limitations, such as high lymphocyte number requirement, degradation of samples, and insufficient standardization due to technical and operator variability. To overcome these limitations, we used a DNA methylation-based quantitative PCR that detects the epigenetic signature of different peripheral blood immune cell subsets (epigenetic quantification). This technique provides relative and absolute immune cell counts applicable to fresh, frozen, or paper-spotted dried blood. Epigenetic measurements are based on a per cell DNA copy number and provide a clear positive or negative signal rather than arbitrarily defined thresholds for "positivity" as in flow cytometry. We hypothesize that epigenetic quantification at day 15 after αβhaplo-HSCT could predict flow-based IR at day 100. Patients were consented at Lucile Packard Children's Hospital (Stanford, CA). Blood was collected between days 10-17 for epigenetic quantification and days 82-124 for flow cytometry. Bisulfite treated DNA underwent qPCR quantification of cell type-specific DNA regions of de-methylation (Baron U et al. Sci Transl Med 2018 Aug 1;10(452):eaan3508). Flow cytometry was performed using directly conjugated antibodies. Absolute cell counts were determined, plotted, and then analyzed using a linear regression model. In the first 5 αβhaplo-HSCT patients evaluated, we found a direct correlation between the epigenetic quantification at day 15 and flow cytometry at day 100 for CD4+ T cells (P=0.01), while the early epigenetic quantification of CD3+ and CD8+ T cells was not informative (Fig. 1). Preliminary data suggest that the use of epigenetic quantification early after αβhaplo-HSCT can predict the IR of CD4+ T cells at day 100 in αβhaplo-HSCT recipients. Ongoing analysis on a larger cohort of both αβhaplo-HSCT and unmanipulated HSCT recipients, will confirm if epigenetic quantification results obtained early post-HSCT can be used as a clinical biomarker of delayed IR and guide physicians in the use of post-HSCT adoptive immunotherapy. [ABSTRACT FROM AUTHOR]

Organ transplantation is an effective way to treat many end-stage diseases. In order to overcome post-transplant rejection, immunosuppressive agents have been widely used, but the long-term survival of transplanted organs still has not been achieved in the clinic. For decades, tolerance is the "holy grail" that transplant immunologists have longed for. The well-known approaches to induce immune tolerance are through adoptively transferred regulatory T cells and achieving chimeric states. In addition, there are a variety of promising potential strategies, including costimulatory blockade, regulating differentiation of immune cell subgroups, adoptive infusion of immunoregulatory cells, using apoptotic cells to induce tolerance, stem cell regenerative medicine to reconstitute tissue and organs, helminthic therapy, using exosomes carrying phagocytic antigen and phagocytic vesicles to induce tolerance, and blocking CD3 and targeted clearance of memory T cells. In this paper, we review the current developments and the potential of these strategies to achieve transplantation tolerance. • Although immunosuppressants are used in organ transplant, the tolerance of transplanted organs still have not been achieved. • Adoptively transferred Tregs and achieving chimeric states are the popular approaches to induce immune tolerance. • There are other promising strategies, such as costimulatory blockade, using apoptotic cells to induce tolerance and so on. • There is still a long way to achieve perfect transplant tolerance. [ABSTRACT FROM AUTHOR]

In this paper, we are concerned with a diffusive viral infection dynamical model with general infection mechanism and distinct dispersal rates. In a general setting in which the model parameters are spatially heterogeneous, it is shown that if ℛ 0 ≤ 1 , the infection-free steady state is globally asymptotically stable; while if ℛ 0 > 1 , the model is uniformly persistent. The asymptotic profiles of the infection steady state are discussed as the dispersal rate of uninfected CD4 + T cells approaches zero by means of the persistence theory of semidynamical systems and the eigenvalue theory of elliptic equations. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is the most common demyelinating disease which mainly impacts the integrity of central nervous system (CNS). MS etiology is not clearly known but genetic, environmental factors and immune system are the most frequently explored risk factors. Adaptive immune responses have a critical role in MS pathogenesis in which auto-reactive T-cells and autoantibodies are main orchestrators. Immune responses are modulated by inhibitory molecules which regulates adaptive system activation and hemostasis interface. These molecules suppress immune responses through inhibition of cytokine secretion and T cell proliferation and subsequently reducing the inflammation and respective damage. Therefore the critical role of inhibitory molecules in regulating the healthy and safe immune responses make them very attractive target for immunotherapy. In this review paper, the role of inhibitory molecules expressed on the various immune cell types in MS pathogenesis and experimental autoimmune encephalomyelitis (EAE) animal model will be summarized. • VISTA is one of the goals in the therapeutic target for MS treatment. • CTLA-4 polymorphisms do not correlate with MS susceptibility. • Modulating Lag-3 can affect the autoimmune disease as well as MS. • TIM3–galectin-9 pathway associated with auto-reactive T cells. • Modulation of PD1 and PD-L1 pathways holds promise in MS therapeutic potential. [ABSTRACT FROM AUTHOR]

• We comment on work by Schinkelshoek et al "H1N1 hemagglutinin-specific HLA-DQ6 restricted CD4+ T cells can be readily detected in narcolepsy type 1 patients and healthy controls. " in J. Neuroimmunology • These authors found no evidence of mimicry between flu hemagglutinin (HA) and Hypocretin (HCRT) • Referring to a paper by Luo et al. Proc. Natl. Acad. Sci. 115(52): E12323-E12332, 2018, we report that by sequencing 100 times more cells we do in fact find evidence for cross reacting TCR sequences, suggesting mimicry. [ABSTRACT FROM AUTHOR]

CD8 T-cell immunity is thought to require helper activity derived from CD4 T cells. Nevertheless, under some circumstances, effective CD8-dependent T-cell responses occur in vivo without CD4 T-cell help. Several recent papers help to explain this paradox and lead to a refined view concerning the role of T helper cells and interleukin-2 receptor signaling in the production of cytotoxic T lymphocytes. [ABSTRACT FROM AUTHOR]

Occasionally, the discovery of a new molecule sheds light on an entire biological system. A good example is the discovery of the tumor necrosis factor (TNF)-related molecule, B-cell-activating factor belonging to the TNF family (BAFF), known also as BLyS, TALL-1, zTNF4 or THANK. A flurry of papers from several groups, describing results from transgenic and knockout mice, animal models and human studies, has shown that BAFF is a crucial molecule involved in B-cell maturation and the development of autoimmunity. Several recent reports add to this exciting story and illustrate some of the formative stages of B-cell maturation and tolerance. [Copyright &y& Elsevier]

In some patients with mycosis fungoides atypical cells ("mycosis cells") are found in the blood. Recently the T-cell membrane characteristics of these atypical cells have been described. In this paper the results of a study of the atypical cells isolated from the lymph nodes and the skin lesions of three patients with mycosis fungoides are presented. Using electron microscopy, it could be demonstrated that the atypical cells formed rosettes with uncoated sheep red blood cells, but not with antibody-complement-coated sheep erythrocytes, indicating the T-cell membrane characteristics of the atypical cells. [ABSTRACT FROM AUTHOR]

Epidermal Langerhans cells are dendritic bone marrow-derived cells which synthesize and express Ia antigens. During the past decade, in vitro studies have demonstrated that they play a critical role in the induction of many types of T-cell responses. Specifically, Langerhans cells are effective antigen-presenting cells in allogeneic and antigen specific proliferative and cytotoxic T-cell responses. This paper reviews these functions and suggests areas of future investigations into the mechanisms involved in T-cell activation by Langerhans cells. [ABSTRACT FROM AUTHOR]