Properties Of Memory Cells Research Articles

Cellular and humoral factors of innate antiviral immunity

The study presents new data on the biological effects of well-known cellular and humoral factors that ensure the functioning of innate immunity. Four mechanisms induced by viruses, which lead to the destruction of inhibitory proteins and trigger the transcription of interferon genes, are described. The paper also presented the order of synthesis of species of interferons and other pro-inflammatory cytokines in the development of an antiviral immune response. This is of great importance because viruses have significantly different resistance to the biological effects of interferons. Interferon lambda played a role in the development of innate immune reactions against many viruses, and the effectiveness of the functioning of the mechanisms of the innate and adaptive immunity in viral infections was evaluated, depending on the state of the stat l, 4, 6 genes and genes of interferon regulators. An interferon-independent variant of the innate immune response in viral infections that occurs a few hours after infection and is associated with chemokine CXCL10 has been described. Data on the most important role of the ubiquitin-proteasome cleavage pathway of proteins and the complement system in the implementation of antiviral effects of innate immunity are also presented. The uniqueness of the microbicidal effects of natural killers, which are realized only in cells that reduced the expression of major histocompatibility complex I molecules, has been established. In addition, natural killers can recognize and do not attack target cells carrying antigens of HLA-E, the sublocus of the major histocompatibility complex I molecules. The natural killers were found to acquire the properties of memory cells. This is facilitated by interleukins 12 and 18. The extracellular neutrophil traps of neutrophils showed microbicidal effects against many viruses. The congenital lymphoid cells have multifaceted effects on the development of an antiviral immune response.

Bcl6 drives stem-like memory macrophages differentiation to foster tumor progression

Cancer development is a long-lasting process during which macrophages play a pivotal role. However, how macrophages maintain their cellular identity, persistence, expanding and pro-tumor property during malignant progression remains elusive. Inspired by the recent report of the activation of stem cell-like self-renewal mechanism in mature macrophages, we postulate that intra-tumoral macrophages might be trained to assume stem-like properties and memory-like activity favoring cancer development. Herein we demonstrated that tumor infiltrating macrophages rapidly converted into the CD11b+F4/80+Ly6C−Bcl6+ phenotype, and adopted stem cell-like properties involving expression of stemness-related genes, long-term persistence and self-renewing. Importantly, Bcl6+ macrophages stably maintained cell identity, gene signature, metabolic profile, and pro-tumor property even after long-term culture in tumor-free medium, which were hence termed stem cell-like memory macrophages (SMMs). Mechanistically, we showed that transcriptional factor Bcl6 co-opted the demethylase Tet2 and the deacetylase SIRT1 to confer the epigenetic imprinting and mitochondrial metabolic traits to SMMs, bolstering the stability and longevity of trained immunity in tumor-associated macrophages (TAMs). Furthermore, tumor-derived redHMGB1 was identified as the priming signal, which, through TLR4 and mTOR/AKT pathway, induced Bcl6-driven program underpinning SMMs generation. Collectively, our study uncovers a distinct macrophage population with a hybrid of stem cell and memory cell properties, and unveils a regulatory mechanism that integrates transcriptional, epigenetic and metabolic pathways to promote long-lasting pro-tumor immunity.

The role of cells of the innate immune system in psoriasis

Psoriasis is an immune-mediated disease with a complex pathogenesis. The close relationship between the development of psoriasis and the adaptive immune response is already known. However, recent data have shown that innate immune cells also play an important role in the development of psoriasis. Congenital lymphoid cells, dendritic cells, T cells, NK cells, and NKT lymphocytes are activated in psoriasis, contributing to disease pathology through IL-17-dependent and independent mechanisms. During disease progression, T cells secrete proinflammatory cytokines that induce and exacerbate the course of psoriasis. T cells have memory cell properties that respond rapidly to secondary stimulation, which contributes to disease relapse. This article presents an overview of recent findings demonstrating the role of innate immunity in psoriasis.

TCAD Simulation of a 3D NAND Memory Utilizing In-Ga-Zn-Oxide: "3D OS NAND" with 4 V Drive, High Endurance and Density

Memory-centric computing has been actively researched for AI application. To achieve this, there are growing demands on memories for high density and high endurance. To demonstrate the application, a variety of emerging memory technologies have been proposed; however, they still have difficulties in achieving a density comparable to NAND flash and in improving endurance.CAAC-IGZO, with a wide bandgap and a heavy hole effective mass, can be applied to a field-effect transistor that is characterized by its extremely-low off-leakage current. Use of CAAC-IGZO FET in non-display fields has been reported in recent years, and 3D NAND utilizing CAAC-IGZO FET has been researched. However, the reported memory cell architecture involves through-dielectric charge trapping in MONOS structures, and has low endurance in the same way as conventional Si-based NAND flash.In view of the above, we propose a 3D OS NAND memory, a vertically-stackable 2Tr-1C memory having CAAC-IGZO FETs. Potentially, this memory not only enjoys main features of NAND flash such as high density and non-volatility, but also achieves a DRAM-like endurance. In this study, we evaluated our novel memory architecture with TCAD Sentaurus produced by Synopsys.The cross section, circuit diagram, and 3D overall structure of the memory cell are shown in Fig. 1(a), Fig. 1(b), and Fig. 1(c), respectively. The 3D OS NAND has a memory cell architecture in which a pair of vertically-positioned transistors on the A-A' plane is connected in series to another pair in the Z-axis direction. Taking advantage of extremely-low off-leakage current of CAAC-IGZO FET, the memory cell is composed of only a switching CAAC-IGZO FET and a MIM capacitor. The timing chart of a string of four memory cells connected in the Z-axis direction is shown in Fig. 1(d). Write operation is performed by sequentially lowering the voltage of WG from the bottom with respect to the Z-axis direction, and read operation is performed by lowering the voltage of CG of the memory cell being read. The retention properties of memory cells to which a checker pattern is written are shown in Fig. 1(e). The device simulation indicates a possibility that a memory cell composed of only an CAAC-IGZO FET and a MIM capacitor achieves a retention time of 109 sec or longer. In this paper, we propose a novel memory architecture with CAAC-IGZO FET by discussing the overview of 3D OS NAND and its write and read performance. Fig. 1(a) Cross section of 3D OS NAND memory cell, (b) circuit diagram of 3D OS NAND memory cell, (c) 3D structure of 3D OS NAND, (d) timing chart of 3D OS NAND, and (d) retention properties of 3D OS NAND Figure 1

Antigen-specific CD8+ memory stem T cells generated from human peripheral blood effectively eradicate allogeneic targets in mice

BackgroundAs the implantation and long-term existence of tumor-specific T cells in host are the prerequisite for adoptive immunotherapy, memory stem T cells (TSCM) with self-renewal and differentiation capacity show the greatest potential to implant and long-term exhibit function in vivo, compared with other T cells of differentiation stages. Hence, tumor-specific TSCM have become potential candidate for adoptive T cell therapy of cancer. Here, we reported a protocol to generate allogeneic antigen-specific CD8+ TSCM cells from human PBLs.MethodsTo prepare allogeneic antigen-specific CD8+ TSCM, we used an LCL named E007 of defined HLA allotyping as simulator, a co-culture of E007 and allogeneic PBLs was carried out in the presence of differentiation inhibitor TWS119 for 7 days. Sorting of proliferation cells ensured the E007-specificity of the prepared TSCM cells. The sorted lymphocytes underwent further expansion by cytokines IL-7 and IL-15 for further 7 days, making the E007-specific CD8 + TSCM expanded in number. The stem cell and T memory cell properties of the prepared CD8+ TSCM were observed in NOD-SCID mice.ResultsOur protocol began with 1 × 107 PBLs and resulted in 2 × 107 E007-specific CD8+ TSCM cells in 2 weeks of preparation. The prepared TSCM cells exhibited a proliferative history and rapid differentiation into effector cells upon the E007 re-stimulation. Importantly, the prepared TSCM cells were able to exist long and reconstitute other T cell subsets in vivo, eradicating the E007 cells effectively after transferred into the LCL burden mice.ConclusionsThis protocol was able to prepare allogeneic antigen-specific CD8+ TSCM cells from human PBLs. The prepared TSCM showed the properties of stem cells and T memory cells. This study provided a reference method for generation of antigen-specific TSCM for T cell adoptive immunotherapy.

IMMUNOLOGICAL MEMORY: THE ROLE OF REGULATORY CELLS (TREGS)

Memory T cells are necessary for development of the immune response and represent one of the most numerous population of human T lymphocytes. On the contrary, suppressive regulatory T cells (Tregs) may terminate the immune response and help to maintain tolerance to self-antigens. These important groups of cells are consisting of different subpopulations and retaining throughout life. However, today there is yet no clear understanding of how the relations between these two groups of cells are formed. In this work we consider possible ways of development and maintenance of CD4+ T cell memory and role of Tregs in these processes. Mechanisms of a differentiation of memory T cells, Tregs and recently described memory Tregs are discussed. The functional and genetic characteristics of these cells are compared. Division of cells according to the functional profile allows drawing parallels between memory T cells and Tregs. These two groups are consisted of central circulating populations (Tc), effector which can migrate toward specific tissues (Te) and tissue-resident cells (Tr), which are staying in peripheral tissues. The similar structural organization of Tregs and memory T cells, existence of transitional forms of tissue-resident Treg subpopulations with properties of memory cells assumes existence of close interrelation between these groups of lymphocytes. The conversion of CD4+ memory T cells into FoxP3-expressing Tregs is one of possible mechanisms of communication between these two groups. The memory Treg-cells with T cell and memory Treg-cell properties can represent a transitional stage of differentiation. On the other side, Treg cells can differentiate independently of memory T cells and accumulate during life in the form of memory Treg cells. The supressor function of Tregs is also necessary as well as function of memory T cells to develop the immune response. It is possible, that a subset of Treg cells undergoes selection in thymus and constitutively express TCR-receptors having affinity with peripheral tissues. Further, these committed cells can be settled into tissues and become tissue-resident Treg cells which maintain regional T cell memory. Tregs can represent the “mirror image” of the structural organization of memory T cells, but with the return sign – the sign of suppression. The quantitative ratio of Tregs and memory T cells (CD4+CD45RO+CD25hiFoxP3+/CD4+CD45RO+CD25-FoxP3-), perhaps, is important criterion for functional assessment of immune system. The balance between these functionally opposite cell subsets has to provide stable functioning of immune system.

Use of NH3 etchant for voids suppression to enhance set cycles in CGeSbTe-based phase change memory devices

As the cell size of phase change memory devices decreases to less than 100nm, the dry etch used for cell patterning becomes extremely critical because of its impact on the properties of memory cells. HBr gas has been known as the etchant that can minimize surface etching damage to GeSbTe-based phase change materials. However, the findings reported herein show that the HBr etch of CGeSbTe (CGST) films causes voids after annealing at temperatures below 400°C due to the vaporization of volatile bromides (GeBr4, SbBr2, and TeBr2) that form when bromine diffuses during the etch. In this investigation, we report on the use of NH3 etchants to suppress the formation of volatile compounds and thereby eliminate void formation in CGST materials. The properties of NH3 etchants were compared to those of HBr etchants as a function of both etch rate and profiles. The effects of void suppression as observed in transmission electron microscopy images of as-etched CGST film after annealing indicate that phase change memory devices etched using an NH3 exhibited enhanced set cycles that were over 108 superior to results of HBr etchants by 2 orders of magnitude.

Infection history determines the differentiation state of human CD8+ T cells.

After the resolution of the acute phase of infection, otherwise quiescent antigen-experienced CD8(+) T cells confer rapid protection upon reinfection with viral pathogens or, in the case of persistent viruses, help to maintain control of the infection. Depending on the type of virus, antigen-specific CD8(+) T cells have distinct traits, ranging from typical memory cell properties in the case of rapidly cleared viruses to immediate effector functions for persistent viruses. We here show that both the differentiation stage, defined by the expression of cell surface markers, such as CD45RA, CCR7, CD28, and CD27, and distinct expression levels of T-bet and eomesodermin (Eomes) predict the functional profile of antigen-experienced CD8(+) T cells. Furthermore, virus-specific CD8(+) T cells targeting different respiratory syncytial virus-, influenza A virus-, Epstein-Barr virus (EBV)-, human cytomegalovirus (hCMV)-, and HIV-1-specific epitopes adopt distinct T-bet and Eomes expression patterns that appear to be installed early during the primary response. Importantly, the associations between surface phenotype, T-bet/Eomes expression levels, and the expression of markers that predict CD8(+) T-cell function change according to viral infection history, particularly against the background of HIV-1 and, to lesser extent, of human cytomegalovirus and/or Epstein-Barr virus infection. Thus, the functionality of human antigen-experienced CD8(+) T cells follows at least two dimensions, one outlined by the surface phenotype and another by the T-bet/Eomes expression levels, which are determined by previous or persistent viral challenges. Functional human CD8(+) T-cell subsets have been defined using surface markers like CD45RA, CCR7, CD28, and CD27. However, the induction of function-defining traits, like granzyme B expression, is controlled by transcription factors like T-bet and Eomes. Here, we describe how T-bet and Eomes levels distinctly relate to the expression of molecules predictive for CD8(+) T-cell function in a surface phenotype-independent manner. Importantly, we found that central memory and effector memory CD8(+) T-cell subsets differentially express T-bet, Eomes, and molecules predictive for function according to viral infection history, particularly so in the context of HIV-1 infection and, to lesser extent, of latent EBV- and/or hCMV-infected, otherwise healthy adults. Finally, we show that the distinct phenotypes and T-bet/Eomes levels of different virus-specific CD8(+) T-cell populations are imprinted early during the acute phase of primary infection in vivo. These findings broaden our understanding of CD8(+) T-cell differentiation.

Circulating T follicular regulatory and helper cells have memory-like properties.

Follicular Tregs (Tfr cells) inhibit antibody production, whereas follicular Th cells (Tfh cells) stimulate it. Tfr cells are found in blood; however, relatively little is known about the developmental signals for these cells or their functions. Here we demonstrated that circulating Tfr and Tfh cells share properties of memory cells and are distinct from effector Tfr and Tfh cells found within lymph nodes (LNs). Circulating memory-like Tfh cells were potently reactivated by DCs, homed to germinal centers, and produced more cytokines than did effector LN Tfh cells. Circulating memory-like Tfr cells persisted for long periods of time in vivo and homed to germinal centers after reactivation. Effector LN Tfr cells suppressed Tfh cell activation and production of cytokines, including IL-21, and inhibited class switch recombination and B cell activation. The suppressive function of this population was not dependent on specific antigen. Similar to LN effector Tfr cells, circulating Tfr cells also suppressed B and Tfh cells, but with a much lower capacity. Our data indicate that circulating memory-like Tfr cells are less suppressive than LN Tfr cells and circulating memory-like Tfh cells are more potent than LN effector Tfh cells; therefore, these circulating populations can provide rapid and robust systemic B cell help during secondary antigen exposure.

IL-10-IL-21-STAT3 axis regulates memory CD8 T cell development (110.9)

Abstract Developing memory CD8 T cells is a paramount goal of many vaccines that will fight infections and cancer. Many types of acute infections can generate robust memory T cells, and therefore there must be a mechanism for instilling memory cell properties into a small portion of the memory precursor effector CD8 T cells and “preserve” their potential to develop into memory cells. However, the signals and genetic pathways that govern this process remain poorly defined. Here we show that the IL-10-IL-21-STAT3 pathway was critical for memory CD8 T cell development after acute LCMV infection. Lack of either IL-10 and IL-21 or STAT3, virus-specific CD8 T cells retained terminal effector (TE) differentiation states and failed to mature into protective memory T cells that contained self-renewing central memory T cells. Expression of BCL-6 and SOCS3 was considerably reduced in STAT3-deficient memory CD8 T cells, and BCL-6- or SOCS3-deficient CD8 T cells also had perturbed memory cell development. Reduced SOCS3 expression rendered STAT3-deficient CD8 T cells hyperresponsive to IL-12, suggesting that the STAT3-SOCS3 pathway helps to insulate memory precursor cells from inflammatory cytokines that drive TE differentiation. Next, we began to dissect the cellular sources of IL-10 and IL-21 and the temporal role of these cytokines in effector and memory CD8 T cell differentiation. This will advance our understanding of cellular mechanisms of memory CD8 T cell fate commitment and maintenance.

Gamma ray effects on flash memory cell arrays

Information stored in flash memories is physically represented by the absence or presence of charge on electrically isolated floating gates. Interaction of gamma rays with the insulators surrounding the floating gate produces effects that degrade the properties of memory cells, possibly leading to the corruption of the stored content. The cumulative nature of these effects is expressed through the total ionizing dose deposited by the gamma rays in the insulators surrounding the floating gate. Relying on both theory and experiment, we examine how the properties of cells in commercially available flash memories affect their sensitivity to gamma rays. Memory samples from several manufacturers, currently available on the market, can be compared with respect to data retention under gamma ray exposure.

Increased Numbers of Preexisting Memory CD8 T Cells and Decreased T-bet Expression Can Restrain Terminal Differentiation of Secondary Effector and Memory CD8 T Cells

Memory CD8 T cells acquire effector memory cell properties after reinfection and may reach terminally differentiated, senescent states ("Hayflick limit") after multiple infections. The signals controlling this process are not well understood, but we found that the degree of secondary effector and memory CD8 T cell differentiation was intimately linked to the amount of T-bet expressed upon reactivation and preexisting memory CD8 T cell number (i.e., primary memory CD8 T cell precursor frequency) present during secondary infection. Compared with naive cells, memory CD8 T cells were predisposed toward terminal effector (TE) cell differentiation because they could immediately respond to IL-12 and induce T-bet, even in the absence of Ag. TE cell formation after secondary (2°) or tertiary infections was dependent on increased T-bet expression because T-bet(+/-) cells were resistant to these phenotypic changes. Larger numbers of preexisting memory CD8 T cells limited the duration of 2° infection and the amount of IL-12 produced, and consequently, this reduced T-bet expression and the proportion of 2° TE CD8 T cells that formed. Together, these data show that over repeated infections, memory CD8 T cell quality and proliferative fitness is not strictly determined by the number of serial encounters with Ag or cell divisions, but is a function of the CD8 T cell differentiation state, which is genetically controlled in a T-bet-dependent manner. This differentiation state can be modulated by preexisting memory CD8 T cell number and the intensity of inflammation during reinfection. These results have important implications for vaccinations involving prime-boost strategies.

Formation of Schottky-type metal/SrTiO3 junctions and their resistive properties

Motivated by the successful use of strontium titanate with different doping metals for memory cells on the basis of resistive switching and the recent findings on the major importance of oxygen vacancy redistribution in this compound, the present work shows the possibility of a non-volatile resistance change memory based on vacancy-doped SrTiO3. The formation of corresponding metal/SrTiO3−δ junctions (δ>0) in an electric field will be discussed as well as the switching between ohmic and Schottky-type contact behavior. A notable hysteresis in the current–voltage characteristics is used to carry out Write, Read, and Erase operations exemplifying the memory cell properties of such junctions. But whereas the electric field-induced formation of Schottky-type junctions is explainable by oxygen vacancy redistribution, the resistive switching needs to be discussed in terms of vacancies serving as electron trap states at the metal/oxide interface.

Transcriptional Repressor Blimp-1 Promotes CD8+ T Cell Terminal Differentiation and Represses the Acquisition of Central Memory T Cell Properties

During acute infections, a small population of effector CD8(+) T cells evades terminal differentiation and survives as long-lived memory T cells. We demonstrate that the transcriptional repressor Blimp-1 enhanced the formation of terminally differentiated CD8(+) T cells during lymphocytic choriomeningitis virus (LCMV) infection, and Blimp-1 deficiency promoted the acquisition of memory cell properties by effector cells. Blimp-1 expression was preferentially increased in terminally differentiated effector and "effector memory" (Tem) CD8(+) T cells, and gradually decayed after infection as central memory (Tcm) cells developed. Blimp-1-deficient effector CD8(+) T cells showed some reduction in effector molecule expression, but primarily developed into memory precursor cells that survived better and more rapidly acquired several Tcm cell attributes, including CD62L and IL-2 expression and enhanced proliferative responses. These results reveal a critical role for Blimp-1 in controlling terminal differentiation and suppressing memory cell developmental potential in effector CD8(+) T cells during viral infection.

Modeling the CD8+ T Effector to Memory Transition in Adoptive T-Cell Antitumor Immunotherapy

Adoptive T-cell therapy with CD8(+) CTLs is often characterized by poor persistence of the transferred T cells and limited effector responses. Improved persistence and therapeutic efficacy have been noted when antigen-activated CD8(+) T cells express properties of memory cells. The current study was undertaken to more precisely characterize the development of memory-like CD8(+) T cells from short-term CTLs in vitro and upon transfer in vivo, including their antitumor activity. Ovalbumin (OVA)-specific OT-I CTLs acquired phenotypic and functional properties of memory cells 2 to 3 days later either by lowering the concentration of antigen to a level that does not support primary responses and providing a survival signal through transgenic Bcl-2 in vitro or simply by transferring early day 3 CTLs to antigen-free lymphoid-replete mice. In lymphoid-replete mice, established OVA-expressing E.G7 tumor was rejected by short-term CTLs that simultaneously acquired memory-like properties in secondary lymphoid tissues, where tumor antigen level remained low. Collectively, these data indicate that CTLs readily converted to memory-like cells upon lowering antigen to a concentration that selectively supports memory responses and suggest that such conversion predicts successful adoptive immunotherapy.

Primer: making sense of T-cell memory

Protective memory is a key property of the immune system. Pathogen-associated molecular patterns of invading organisms deliver signals to pattern-recognition receptors that activate the innate immune system. Ligation of the T-cell receptor by peptides bound to MHC antigens and presented by dendritic cells, together with signals produced by the activated innate immune system, initiate T-cell responses. The nature of the T-cell response, consisting of phases of clonal expansion and contraction, and differentiation to effector and memory cells, however, is determined both by the properties of the antigen and the co-stimuli produced by the innate immune system. Short-lived effector and longer-lived memory T cells are generated during primary responses; after the death of most of the effectors, memory cells remain. Memory cells are heterogeneous in phenotype and function; subsets include the relatively quiescent central and more activated effector memory cells, as well as cells able to promote inflammation, help antibody production or regulate other immune responses. Understanding the properties of memory cells will help in the rational design of vaccines for 'difficult' organisms or cancer, as well as immunotherapies for autoimmune diseases.

Effector CD8 T cells transit to memory cells in the presence of tumor-associated antigen (85.17)

Abstract It is difficult to study the time frame and requirements for antigen removal as CD8 T effector cells transit to memory cells during an immune response because memory cells only readily appear after contraction of the effector response and clearance of antigen. To overcome these limitations, we have modeled the effector to memory transition in vitro and by the adoptive transfer of effector CTL to normal mice. When OVA-specific OT-I CTL were cultured in IL-15 without antigen, they acquired phenotypic and functional properties of memory cells 48 hr later. Such memory conversion occurred in the presence of 0.01 nM OVA peptide and APC, a dose that only induces a strong recall response, but not at a higher dose (0.1 nM) that readily activates naïve OT-I T cells. Following adoptive transfer of OT-I CTL to antigen-free normal mice, OT-I effector cells developed into central memory-like cells by 3 days post-transfer. Upon adoptive transfer to mice bearing the OVA-expressing E.G7 tumor, the OT-I CTL effector cells also readily converted to memory-like cells by day 3 post-transfer while the effector cells rejected the tumor. However, under conditions where the tumor was not cleared, memory production was impaired. Collectively, these data suggest that some CTL rapidly convert to memory cells concurrent with an effector response, without complete clearance of antigen, provided that antigen level is not too high. (Supported by the NIH)

All Memory Lymphocytes Share a Common Differentiation Program.

Although memory lymphocytes in CD4, CD8 and B cell lineages are characterized by a strikingly diverse array of functions and phenotypes, they share common properties of longevity, lowered response threshold and the ability to self-renew. The development of these memory functions is essential for immunity to pathogens and tumors, but it is not known how diverse lineages acquire these same properties. We therefore studied the transcriptional profile of memory differentiation to determine whether the development of memory in disparate lineages involves a common differentiation program. To identify a core signature of memory differentiation, we used cross-species genomic analysis to identify genes differentially expressed by both human and murine memory CD8 T cells compared to their naive precursors. We identified 220 genes significantly increased in human memory-phenotype cells, and found this signature to be highly conserved in two different TCR transgenic murine models of memory differentiation (P<0.001). Our analysis thus revealed an evolutionarily conserved transcriptional signature of CD memory differentiation. Several of the genes in this signature are known to be required for CD8 memory development, while others are novel markers of memory differentiation. We validated the signature at the protein and functional level, and demonstrated that it is highly enriched in the gene expression profiles of human CD8 T cells specific for CMV, influenza and EBV, suggesting that diverse viral pathogens can induce a similar differentiation program. We next tested whether this conserved signature is necessary for memory cells to be fully functional. To address this question, we studied memory differentiation in TCR transgenic T cells responding acute or chronic LCMV infection. Adult mice resolve an acute LCMV infection and then exhibit long-term CD8 T cell memory. In contrast, chronic LCMV infection results in exhausted CD8 cells that fail to demonstrate the properties of memory cells. Hierarchical clustering of the memory signature genes showed marked differences between functional memory cells and virally-exhausted T cells. Thus the signature of memory differentiation is disrupted in CD8 cells that fail to manifest the properties of memory. Finally, we tested the conserved CD8 memory signature in gene expression profiles of human memory CD4 and memory B cells compared to their naïve precursors. We found that the CD8 memory signature was highly enriched not only in CD4 memory (P<0.001) but also in B cell memory (P<0.001). Thus a single transcriptional signature is a general feature of memory differentiation in CD8, CD4 and B cells, and disruption of this signature is associated with defective T cell memory. Analysis of the regulation of this transcriptional program may help identify the mechanisms governing memory differentiation. Our data represent a novel approach to predicting the function of antigen-specific memory cells in vivo, and suggest that drugs which target this single differentiation program could profoundly influence the formation of immunologic memory.

Si O 2 ∕ Si 3 N 4 ∕ Al 2 O 3 stacks for scaled-down memory devices: Effects of interfaces and thermal annealing

Effects of interfaces and thermal annealing on the electrical performance of the SiO2∕Si3N4∕Al2O3 (ONA) stacks in nonvolatile memory devices were investigated. The results demonstrated the principal role of Si3N4∕Al2O3 and Al2O3/metal-gate interfaces in controlling charge retention properties of memory cells. Memory devices that employ both electron and hole trappings were fabricated using a controlled oxidation of nitride surface prior to the Al2O3 growth, a high-temperature annealing of the ONA stack in the N2+O2 atmosphere, and a metal gate electrode having a high work function (Pt). These devices exhibited electrical performance superior to that of their existing SiO2∕Si3N4∕SiO2 analogs.

Homeostatic proliferation is a barrier to transplantation tolerance.

Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation, may induce acquisition of functional memory T cells. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.