Functional Memory Cells Research Articles

Cellular memory function from 3D to 2D: Three-dimensional high density collagen microfiber cultures induce their resistance to reactive oxygen species

Cell properties generally change when the culture condition is changed. However, mesenchymal stem cells cultured on a hard material surface maintain their differentiation characteristics even after being cultured on a soft material surface. This phenomenon suggests the possibility of a cell culture material to memorize stem cell function even in changing cell culture conditions. However, there are no reports about cell memory function in three-dimensional (3D) culture. In this study, colon cancer cells were cultured with collagen microfibers (CMF) in 3D to evaluate their resistance to reactive oxygen species (ROS) in comparison with a monolayer (2D) culture condition and to understand the effect of 3D-culture on cell memory function. The ratio of ROS-negative cancer cells in 3D culture increased with increasing amounts of CMF and the highest amount of CMF was revealed to be 35-fold higher than that of the 2D condition. The ROS-negative cells ratio was maintained for 7 days after re-seeding in a 2D culture condition, suggesting a 3D-memory function of ROS resistance. The findings of this study will open up new opportunities for 3D culture to induce cell memory function.

Abstract 6353: AM105: A novel bispecific antibody with Anti 4-1BB affibodies and EGFR antibody

Abstract T cell engaging bispecific antibodies have emerged as promising treatments for hematologic malignancies. While most antibodies are CD3-based, offering therapeutic benefits, they are often associated with severe side effects and limited efficacy in solid tumors. To address these challenges, we present AM105, a groundbreaking anti 4-1BB affibodies based bispecific antibody designed to target EGFR. We carefully engineered AM105 with distinct binding affinities for EGFR (KD = 1.8 nM) and 4-1BB (KD = 60 nM), favoring EGFR binding. Affibody specificity was confirmed through a cross-reactivity test with proteins of TNF-receptor superfamily and 21 cell lines expressing 4-1BB or not. In cytotoxicity assays, AM105 exhibited superior tumor cell killing compared to cetuximab, particularly in EGFR-expressing cell lines. Notably, AM105 displayed remarkable efficacy in cell lines harboring RAS and/or BRAF mutations, traditionally unresponsive to EGFR-targeting treatments. In vivo experiments utilizing humanized 4-1BB mice demonstrated AM105's exceptional tumor cell elimination compared to cetuximab. The anti-tumor effects persisted even in the face of new tumor cell introductions, suggesting the induction of T cell memory function. Our findings collectively establish AM105 as a potent therapeutic agent with strong anti-tumor T cell activity. The unique 4-1BB based Affibodies (AffiMab format) of AM105 holds promise for addressing the limitations of current bispecific antibodies, positioning it as a potential breakthrough in cancer immunotherapy. Citation Format: Dong-Wook Kim, Hyun-Jong Lee, Seong Yeol Kim, Min Yoon, Youngha Lee, In-Sik Hwang, Yoon Lee, Jong-Hoon Kim, Jong-Seo Lee. AM105: A novel bispecific antibody with Anti 4-1BB affibodies and EGFR antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6353.

OP 4.4 – 00018 HIV reservoir burden associates with numbers of HIV-specific CD8+ T cells under long-term antiretroviral therapy and prevents them from differentiating into functional memory cells

OP 4.4 – 00018 HIV reservoir burden associates with numbers of HIV-specific CD8+ T cells under long-term antiretroviral therapy and prevents them from differentiating into functional memory cells

Adrenergic signaling controls early transcriptional programs during CD8+ T cell responses to viral infection.

Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the β2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating the differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Rα in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.

Third generation CAR T cells form polyfunctional long-lived memory and protect from solid-tumor relapse in an immunocompetent murine model

Abstract Effector CAR T cell persistence and transition to memory have been widely associated with long-term protection from hematological tumor relapse. In the context of solid tumors, anti-tumor T cell exhaustion in the tumor microenvironment (TME) leads to T cell dysfunction and impaired memory formation. However, in solid tumor models a vast number of infused CAR T cells traffic to lymphoid organs (such as spleen and nondraining lymph nodes), which are bereft of CAR-antigen. The fate of these CAR T cells which have undergone ex vivo activation, viral transduction, and expansion regimens prior to transfer back into patients remains unclear. Using a third generation CAR targeting human(h)CD19t, and syngeneic murine tumor lines expressing hCD19t tumor-associated antigen, we show that CAR T cells residing in antigen-free sites of tumor-bearing immunocompetent mice transition to fully functional memory cells. Using viral infection-induced memory T cells as a benchmark, memory CAR T cells displayed hallmark memory characteristics including homeostatic proliferation, rapid polyfunctional cytokine production upon restimulation, and secondary expansion in response to cognate antigenic stimulation. Finally, memory CAR T cells in naive mice, or in mice with primary tumor remission, were protected against lethal rechallenge with heterologous hCD19t-expressing tumors. Results from this study are among the first to directly compare canonical virus-induced memory T cells with memory CAR T cells, and provide valuable insight into the characteristics and function of memory CAR T cells in an immunocompetent model for solid tumors. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number F32CA265056, and the Pediatric Cancer Research Foundation

Persistent Overactive Cytotoxic Immune Response in a Spanish Cohort of Individuals With Long-COVID: Identification of Diagnostic Biomarkers.

Long-COVID is a new emerging syndrome worldwide that is characterized by the persistence of unresolved signs and symptoms of COVID-19 more than 4 weeks after the infection and even after more than 12 weeks. The underlying mechanisms for Long-COVID are still undefined, but a sustained inflammatory response caused by the persistence of SARS-CoV-2 in organ and tissue sanctuaries or resemblance with an autoimmune disease are within the most considered hypotheses. In this study, we analyzed the usefulness of several demographic, clinical, and immunological parameters as diagnostic biomarkers of Long-COVID in one cohort of Spanish individuals who presented signs and symptoms of this syndrome after 49 weeks post-infection, in comparison with individuals who recovered completely in the first 12 weeks after the infection. We determined that individuals with Long-COVID showed significantly increased levels of functional memory cells with high antiviral cytotoxic activity such as CD8+ TEMRA cells, CD8±TCRγδ+ cells, and NK cells with CD56+CD57+NKG2C+ phenotype. The persistence of these long-lasting cytotoxic populations was supported by enhanced levels of CD4+ Tregs and the expression of the exhaustion marker PD-1 on the surface of CD3+ T lymphocytes. With the use of these immune parameters and significant clinical features such as lethargy, pleuritic chest pain, and dermatological injuries, as well as demographic factors such as female gender and O+ blood type, a Random Forest algorithm predicted the assignment of the participants in the Long-COVID group with 100% accuracy. The definition of the most accurate diagnostic biomarkers could be helpful to detect the development of Long-COVID and to improve the clinical management of these patients.

The Phosphorylation State of Ezh2 Determines Its Capacity to Maintain CD8+ Memory T Cells for Antitumor Immunity

Memory T cells are under active investigation in the context of inhibitory checkpoint blockade therapy and vaccination. In adoptive cell therapies (ACT), minimally differentiated CD8+ T cells, including naïve and central memory T cells, exhibit superior persistence and enhanced antitumor activity compared with highly differentiated effector T cells. Thus, developing strategies to enrich minimally differentiated subsets in cellular products could significantly enhance efficacy and durability of ACT. T cell signal strength, along with costimulatory signals and cytokines, are known to substantially shape the amplitude and quality of the T cell response. Downstream of these signals, epigenetic regulation is thought to critically mold transcriptional programs of memory precursors, however the specific epigenetic regulator(s) that establish and maintain these states are not well characterized. We report that Ezh2 is a key molecular gatekeeper for generation of memory CD8+ T cells, acting to both restrain terminal differentiation and maintain recall response capability. Using experimental ACT models, we found that transfer of melanoma-associated antigen gp100-specific CD8+ T cell receptor transgenic Pmel-1 cells repressed the growth of pre-established B16 melanoma. In contrast, loss of Ezh2 in Pmel-1 T cells failed to repress the tumor growth. Ezh2 deficiency caused a preferential decrease of the central memory precursor (TCMP) pool independent of cell apoptosis early during expansion phase (3 days post-stimulation), while markedly increasing the fraction of terminal effector differentiation. Seven days after priming, Ezh2-deficient CD8+ T cells exhibited increased apoptosis, decreased generation of mature memory T cells and impaired recall response capability upon rechallenge with tumor-associated antigen. Since both the first division of activated CD8+ T cells and their subsequent differentiation early after antigen priming may influence the ratio of TCMP and effector cells, our findings suggest that Ezh2 is important for preserving the TCMP pool and restraining precocious terminal differentiation. Genome-wide gene profiling analysis and functional assessment revealed that Ezh2 achieved these effects by orchestrating the expression of transcription factors critical for effector and memory differentiation. Ezh2 activated Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. However, these data could not explain our previous observations (Blood 2012, Blood 2013, Blood 2017) that during the immune response, normal CD8+ T cells expressed high levels of Ezh2 upon antigen activation, yet, they still underwent a “programmed” differentiation into terminal effector cells. We hypothesized that Ezh2 may undergo a chemical modification capable of altering its function in regulating memory in T cells. Our chromatin immunoprecipitation analysis showed that Ezh2 was dissociated from the promoter regions of these key transcription factors (e.g., Id3, Id2, Prdm1 and Eomes), which occurred 3 days after activation and persisted throughout 7 days of in vitro stimulation. This decreased presence of Ezh2 was paralleled by a reduction of H3K27me3 at the Prdm1 and Eomes loci. In these proliferating T cells, active Akt mediated phosphorylation of Ezh2. Inhibiting Akt activity significantly increased the amount of Ezh2 and H3K27me3 at the promoter regions of Id3, Id2, Eomes and Prdm1 loci. Furthermore, we found that retroviral engineering CD8+ T cells with Akt-phosphorylation-resistant Ezh2 significantly enhanced their generation of long-lasting memory T cells and antitumor activity in vivo. In conclusion, our findings are conceptually and translationally innovative, because they identify the importance of Ezh2 in regulating memory formation and function, and discover a transcription factor network targeted by Ezh2 crucial for regulating the balanced generation of effector and memory T cells. Furthermore, these findings illuminate the Akt-dependent signaling mechanisms responsible for controlling Ezh2-mediated epigenetic control of step-wise differentiation of effector and memory T cells. We propose that Akt-mediated phosphorylation of Ezh2 is a critical target to potentiate anti-tumor immunotherapeutic strategies. DisclosuresNo relevant conflicts of interest to declare.

Peripheral Cellular Immunome Reveals Heterogeneity Spanning Myeloma Spectrum Diseases

INTRODUCTION: Progression from precursor states, termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), to multiple myeloma (MM) is facilitated by cross-talk between malignant plasma cells and cellular/soluble components of the immunosuppressive bone marrow milieu, which promotes angiogenesis, bone destruction and immune-impairment. In support of this view, the frequencies of several peripheral immune cell subsets have been shown to be affected by the disease state. We hypothesized that beyond numerical alterations, activation and differentiation state of circulating innate and adaptive immune cell subsets determines progression from pre-malignant to malignant stage.METHODS: We compared multiple compartments of immune cell subsets in the peripheral blood samples of patients with MGUS (n=7), SMM (n=4) and MM (n=7) enrolled on an IRB-approved prospective biospecimen collection protocol of plasma cell disorders. Peripheral blood mononuclear cells obtained from each subject were immunophenotyped using two 14-color flow cytometry panels. Broadly, immune subsets surveyed included NK cell (mature and immature), NK-T cell, γδ T cell (δ9+γ2- and δ9-γ2- subsets), conventional CD4 and CD8 T cell (effector, effector memory and central memory) and regulatory T cell. Expression of activation, inhibition and maturation markers including NKG2A, NKG2D, KIR3D4, KIR2DS4, CD25, CD38, PD1, and Tim3 was analyzed in all relevant subsets. In total 62 immune variables (cell lineage and functional markers) were generated. For comparisons between MGUS, SMM and MM, one-way ANOVA was used. Unsupervised hierarchical cluster analysis was then applied to all samples with selected variables that were differentially expressed among three groups (p<0.1 by ANOVA) using WPGMA and Euclidean distances. Pair-wise comparisons between MGUS+SMM versus MM or MGUS versus SMM+MM were performed using Welch's t-test.RESULTS: Overall, distribution and functional state of three main immune cell lineages - NK cell, CD4+ T and CD8+ T cell - were altered across MGUS, SMM and MM. Compared to subjects with MGUS and SMM, MM patients had fewer circulating NK cells (p=0.007) with a noticeable shift in NK maturation (Immature/mature NK ratio approximately 3 to 1 for MGUS and SMM vs. 1 to 1 for MM, p=0.015). Mature NK phenotype was confirmed by higher expression of NKG2D on NK cell in MM patients (p=0.041). MGUS and SMM subjects shared an increased expression of immune checkpoints Tim3 (p=0.005) on peripheral CD4+ T effector cells and PD1 (p= 0.012) on functional memory cells, compared with MM patients. Levels of circulating activated CD8 T effector cells were increased in SMM and MM patents compared with MGUS subjects (p<0.001). Unsupervised hierarchical clustering with ten immune variables that were differentially expressed among three groups separated 7/7 MM patients and 9/11 MGUS and SMM subjects (Figure).CONCLUSION: Transition from MGUS and SMM to MM is associated with systemic immune alterations in the functional state of innate (NK) and adaptive (CD4 and CD8 effectors) immune cell subsets. This proof of concept study suggests a role of the peripheral cellular immunome as a possible biomarker that might allow for identification of a subset of MGUS and SMM subjects with a high risk of progression to active MM. We are evaluating this approach prospectively in a larger cohort of patients, including the clonality of the T cell repertoire. [Display omitted] DisclosuresBhutani:Prothena Therapeutics: Research Funding; Amgen: Speakers Bureau; BMS: Speakers Bureau; Takeda Oncology: Speakers Bureau. Voorhees:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Usmani:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Array BioPharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Landscape of Exhausted Virus-Specific CD8 T Cells in Chronic LCMV Infection

A hallmark of chronic infections is the presence of exhausted CD8 Tcells, characterized by a distinct transcriptional program compared with functional effector or memory cells, co-expression of multiple inhibitory receptors, and impaired effector function, mainly driven by recurrent Tcell receptor engagement. In the context of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, most studies focused on studying splenic virus-specific CD8 Tcells. Here, we provide a detailed characterization of exhausted CD8 Tcells isolated from six different tissues during established LCMV infection, using single-cell RNA sequencing. Our data reveal that exhausted cells are heterogeneous, adopt organ-specific transcriptomic profiles, and can be divided into five main functional subpopulations: advanced exhaustion, effector-like, intermediate, proliferating, or memory-like. Adoptive transfer experiments showed that these phenotypes are plastic, suggesting that the tissue microenvironment has a major impact in shaping the phenotype and function of virus-specific CD8 Tcells during chronic infection.

PD-1 Signals are Critical for Homeostatic Maintenance of Memory CD8 T Cells

Abstract Inhibitory signaling in dysfunctional CD8 T cells through the PD-1 axis is well established in chronic viral infections and cancers. PD-1 is also transiently induced to high levels during priming of acute infections and immunizations, yet its impact on the development of long-lived antigen-independent T cell memory remains unclear. Here we show that in addition to its expected role in restraining clonal expansion, PD-1 expression on antigen-specific CD8 T cells during priming and activation is critically required for the development of a durable CD8 T cell memory pool after antigen clearance. Loss of T cell-specific PD-1 signaling led to increased contraction and a striking defect in antigen-independent renewal of memory CD8 T cells in response to homeostatic cytokine signals, thus resulting in attrition and near ablation of the memory pool over time. Notably, in the setting of PD-1 checkpoint blockade immunotherapy of chronic viral infection, while the exhausted CTLs expectedly regained function, the pre-existing pool of resting functional memory cells established in response to a previously administered vaccine underwent attrition. Metabolically, PD-1 signals were necessary for regulating the critical balance of anabolic glycolysis and fatty acid oxidation programs through mTOR to meet the bioenergetics needs of quiescent memory. These studies define PD-1 as a key metabolic regulator of protective T cell immunity, and have potential clinical implications for pre-existing T cell memory to prior infections and vaccinations during PD-1 checkpoint-blockade immunotherapy in cancer.

Activity-Dependent Plasticity at Associative Memory Cells in the Prefrontal Cortex

In addition to structural and functional alternations of neurons during their recruitment to be associative memory cells, these associative memory cells undergo the functional plasticity in response to their activity, called as recruitment-relevant plasticity and activity-dependent plasticity, respectively (Associative Memory Cells: Basic Units of Memory Trace by Jin-Hui Wang 2019). Here, we report the features of activity-dependent plasticity at associative memory cells studied by two-photon cell imaging. After the learning of triple associated signals (pair-stimulations by odor, whisker tactile and tail warming-up), secondary associative memory cells in response to these signals are recruited in the prefrontal cortex. The portion of functional associative memory cells is upregulated by intensive activity in one of three synaptic inputs or their combinations. When whisker, odor or tail stimulus is given intensively, the activity levels of these associative memory cells show low-to-high or high-to-low in response to original cues, especially activity-dependent depression in response to homosynaptic signal and activity-dependent potentiation in response to heterosynaptic signal. When whisker, odor and tail stimulations are given simultaneously, these associative memory cells express activity-dependent potentiation in response to all these input signals. The upregulated activities of norepinephrine and serotonin in the central nervous system strengthen the recruitment, the functional strength and the activity-dependent plasticity of associative memory cell in response to homosynaptic and heterosynaptic signals. As activity-dependent plasticity at associative memory cells occurs immediately after their activation, our results may be due to a possibility that the new synapses formed on associative memory cells during associative learning can be upregulated and downregulated between active state and inactive state, in which their intensive activities and monoamine neurotransmitters are critical modulators. The results can explain activity-related memory strengthening and the role of the arousal system through norepinephrine and serotonin in memory.

Response to Anti-Bcma CAR T Cell Therapy Correlates with T Cell Exhaustion and Activation Status in T Cells at Baseline in Myeloma

Response to Anti-Bcma CAR T Cell Therapy Correlates with T Cell Exhaustion and Activation Status in T Cells at Baseline in Myeloma

Inkjet Printing of Functional Electronic Memory Cells: A Step Forward to Green Electronics.

Nowadays, the environmental issues surrounding the production of electronics, from the perspectives of both the materials used and the manufacturing process, are of major concern. The usage, storage, disposal protocol and volume of waste material continue to increase the environmental footprint of our increasingly “throw away society”. Almost ironically, society is increasingly involved in pollution prevention, resource consumption issues and post-consumer waste management. Clearly, a dichotomy between environmentally aware usage and consumerism exists. The current technology used to manufacture functional materials and electronic devices requires high temperatures for material deposition processes, which results in the generation of harmful chemicals and radiation. With such issues in mind, it is imperative to explore new electronic functional materials and new manufacturing pathways. Here, we explore the potential of additive layer manufacturing, inkjet printing technology which provides an innovative manufacturing pathway for functional materials (metal nanoparticles and polymers), and explore a fully printed two terminal electronic memory cell. In this work, inkjetable materials (silver (Ag) and poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS)) were first printed by a piezoelectric Epson Stylus P50 inkjet printer as stand-alone layers, and secondly as part of a metal (Ag)/active layer (PEDOT:PSS)/metal (Ag) crossbar architecture. The quality of the individual multi-layers of the printed Ag and PEDOT:PSS was first evaluated via optical microscopy and scanning electron microscopy (SEM). Furthermore, an electrical characterisation of the printed memory elements was performed using an HP4140B picoammeter.

Cell Fate and Developmental Regulation Dynamics by Polycomb Proteins and 3D Genome Architecture.

Targeted transitions in chromatin states at thousands of genes are essential drivers of eukaryotic development. Therefore, understanding the in vivo dynamics of epigenetic regulators is crucial for deciphering the mechanisms underpinning cell fate decisions. This review illustrates how, in addition to its cell memory function, the Polycomb group of transcriptional regulators orchestrates temporal, cell and tissue-specific expression of master genes during development. These highly sophisticated developmental transitions are dependent on the context- and tissue-specific assembly of the different types of Polycomb Group (PcG) complexes, which regulates their targeting and/or activities on chromatin. Here, an overview is provided of how PcG complexes function at multiple scales to regulate transcription, local chromatin environment, and higher order structures that support normal differentiation and are perturbed in tumorigenesis.

Spontaneous Proliferation of CD4+ T Cells in RAG-Deficient Hosts Promotes Antigen-Independent but IL-2-Dependent Strong Proliferative Response of Naïve CD8+ T Cells.

The fast and intense proliferative responses have been well documented for naïve T cells adoptively transferred into chronic lymphopenic hosts. This response known as spontaneous proliferation (SP), unlike antigen-independent lymphopenia-induced proliferation (LIP), is driven in a manner dependent on antigens derived from commensal microbiota. However, the precise nature of the SP response and its impact on homeostasis and function for T cells rapidly responding under this lymphopenic condition are still unclear. Here we demonstrate that, when naïve T cells were adoptively transferred into specific pathogen-free (SPF) but not germ-free (GF) RAG−/− hosts, the SP response of these cells substantially affects the intensity and tempo of the responding T cells undergoing LIP. Therefore, the resulting response of these cells in SPF RAG−/− hosts was faster and stronger than the typical LIP response observed in irradiated B6 hosts. Although the intensity and tempo of such augmented LIP in SPF RAG−/− hosts were analogous to those of antigen-dependent SP, the former was independent of antigenic stimulation but most importantly, dependent on IL-2. Similar observations were also apparent in other acute lymphopenic settings where antigen-dependent T cell activation can strongly occur and induce sufficient levels of IL-2 production. Consequently, the resulting T cells undergoing IL-2-driven strong proliferative responses showed the ability to differentiate into functional effector and memory cells that can control infectious pathogens. These findings therefore reveal previously unappreciated role of IL-2 in driving the intense form of T cell proliferative responses in chronic lymphopenic hosts.

Immunity and longevity.

The role of immune system is to protect the organism from the not built-in program-like alterations inside and against the agents penetrating from outside (bacteria, viruses, and protozoa). These functions were developed and formed during the evolution. Considering these functions, the immune system promotes the lengthening of lifespan and helps longevity. However, some immune functions have been conveyed by men to medical tools (e.g.,pharmaceuticals, antibiotics, and prevention), especially in our modern age, which help the struggle against microbes, but evolutionarily weaken the immune system. Aging is a gradual slow attrition by autoimmunity, directed by the thymus and regulated by the central nervous system and pineal gland. Considering this, thymus could be a pacemaker of aging. The remodeling of the immune system, which can be observed in elderly people and centenarians, is probably not a cause of aging, but a consequence of it, which helps to suit immunity to the requirements. Oxidative stress also helps the attrition of the immune cells and antioxidants help to prolong lifespan. There are gender differences in the aging of the immune system as well as in the longevity. There is an advantage for women in both cases. This can be explained by hormonal differences (estrogens positively influences both processes); however, social factors are also not excluded. The endocrine disruptor chemicals act similar to estrogens, like stimulating or suppressing immunity and provoking autoimmunity; however, their role in longevity is controversial. There are some drugs (rapamycin, metformin, and selegiline) and antioxidants (as vitamins C and E) that prolong lifespan and also improve immunity. It is difficult to declare that longevity is exclusively dependent on the state of the immune system; however, there is a parallelism between the state of immune system and lifespan. It seems likely that there is not a real decline of immunity during aging, but there is a remodeling of the system according to the claims of senescence. This is manifested in the remaining (sometimes stronger) function of memory cells in contrast to the production and number of the new antigen-reactive naive T-cells.

Immunological memory cells.

This article reviews immunological memory cells, currently represented by T and B lymphocytes and natural killer (NK) cells, which determine a rapid and effective response against a second encounter with the same antigen. Among T lymphocytes, functions of memory cells are provided by their subsets: central memory, effector memory, tissue-resident memory, regulatory memory and stem memory T cells. Memory T and B lymphocytes have an essential role in the immunity against microbial pathogens but are also involved in autoimmunity and maternal-fetal tolerance. Furthermore, the evidence of immunological memory has been established for NK cells. NK cells can respond to haptens or viruses, which results in generation of antigen-specific memory cells.T, B and NK cells, which have a role in immunological memory, have been characterized phenotypically and functionally. During the secondary immune response, these cells are involved in the reaction against foreign antigens, including pathogens, and take part in autoimmune diseases, but also are crucial to immunological tolerance and vaccine therapy.

Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumor immunity

Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8+ T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies.

Tristate Memory Cells Using Double-Peaked Fin-Array III–V Tunnel Diodes Monolithically Grown on (001) Silicon Substrates

We demonstrate functional tristate memory cells using multipeaked GaAs/InGaAs fin-array tunnel diodes grown on exact (001) Si substrates. On-chip connection of single-peaked tunnel diode arrays produces I–V characteristics with multiple negative-differential resistance regions. We designed and fabricated two types of tristate memory cells. In one design, a double-peaked tunnel diode was used as the drive, and a reverse-biased single-peaked tunnel diode was used as the load. In the other design, the tristate memory cell was realized by the series connection of two forward-biased single-peaked tunnel diodes.

TCR stimulation strength is inversely associated with establishment of functional brain-resident memory CD8 T cells during persistent viral infection.

Establishing functional tissue-resident memory (TRM) cells at sites of infection is a newfound objective of T cell vaccine design. To directly assess the impact of antigen stimulation strength on memory CD8 T cell formation and function during a persistent viral infection, we created a library of mouse polyomavirus (MuPyV) variants with substitutions in a subdominant CD8 T cell epitope that exhibit a broad range of efficiency in stimulating TCR transgenic CD8 T cells. By altering a subdominant epitope in a nonstructural viral protein and monitoring memory differentiation of donor monoclonal CD8 T cells in immunocompetent mice, we circumvented potentially confounding changes in viral infection levels, virus-associated inflammation, size of the immunodominant virus-specific CD8 T cell response, and shifts in TCR affinity that may accompany temporal recruitment of endogenous polyclonal cells. Using this strategy, we found that antigen stimulation strength was inversely associated with the function of memory CD8 T cells during a persistent viral infection. We further show that CD8 TRM cells recruited to the brain following systemic infection with viruses expressing epitopes with suboptimal stimulation strength respond more efficiently to challenge CNS infection with virus expressing cognate antigen. These data demonstrate that the strength of antigenic stimulation during recruitment of CD8 T cells influences the functional integrity of TRM cells in a persistent viral infection.