Long-term Memory Cells Research Articles

Therapeutic In Situ Cancer Vaccine Using Pulsed Stereotactic Body Radiotherapy-A Translational Model.

Both radiation and cancer therapeutic vaccine research are more than 100 years old, and their potential is likely underexplored. Antiangiogenics, nanoparticle targeting, and immune modulators are some other established anticancer therapies. In the meantime, immunotherapy usage is gaining momentum in clinical applications. This article proposes the concept of a pulsed/intermittent/cyclical endothelial-sparing single-dose in situ vaccination (ISVRT) schedule distinguishable from the standard therapeutic stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) plans. This ISVRT schedule can repeatedly generate tumor-specific neoantigens and epitopes for primary and immune modulation effects, augment supplementary immune enhancement techniques, activate long-term memory cells, avoid extracellular matrix fibrosis, and essentially synchronize with the vascular normalized immunity cycle. The core mechanisms of ISVRT impacting in situ vaccination would be optimizing cascading antigenicity and adjuvanticity. The present proposed hypothesis can be validated using the algorithm presented. The indications for the proposed concept are locally progressing/metastatic cancers that have failed standard therapies. Immunotherapy/targeted therapy, chemotherapy, antiangiogenics, and vascular-lymphatic normalization are integral to such an approach.

Biapenem, a Carbapenem Antibiotic, Elicits Mycobacteria Specific Immune Responses and Reduces the Recurrence of Tuberculosis.

Tuberculosis (TB) still tops the list of global health burdens even after COVID-19. However, it will sooner transcend the current pandemic due to the prevailing risk of reactivation of latent TB in immunocompromised individuals. The indiscriminate misuse and overuse of antibiotics have resulted in the emergence of deadly drug-resistant variants of Mycobacterium tuberculosis (M.tb). This study aims to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM) in generating long-lasting immunity against TB. BPM treatment significantly boosted the activation status of the innate immune arm-macrophages by augmenting p38 signaling. Macrophages further primed and activated the adaptive immune cells CD4+ and CD8+ T-cells in the lung and spleen of the infected mice model. Furthermore, BPM treatment significantly amplified the polarization of T lymphocytes toward inflammatory subsets, such as Th1 and Th17. The treatment also helped generate a long-lived central memory T-cell subset. The generation of central memory T lymphocyte subset upon BPM treatment in the murine model led to a significant curtailing in the recurrence of TB due to reactivation and reinfection. These results suggest the potentiality of BPM as a potent adjunct immunomodulator to improve host defense against M.tb by enriching long-term protective memory cells. IMPORTANCE Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) tops the list of infectious killers around the globe. The emergence of drug-resistant variants of M.tb has been a major hindrance toward realizing the "END TB" goal. Drug resistance has amplified the global burden toward the quest for novel drug molecules targeting M.tb. Host-directed therapy (HDT) offers a lucrative alternative to tackle emerging drug resistance and disease relapse by strengthening the host's immunity. Through our present study, we have tried to characterize the functionality of the carbapenem antibiotic-Biapenem (BPM). BPM treatment significantly augmented long-lasting immunity against TB by boosting the innate and adaptive immune arms. The generation of long-lived central memory T lymphocyte subset significantly improved the disease outcome and provided sterilizing immunity in the murine model of TB. The present investigation's encouraging results have helped us depict BPM as a potent adjunct immunomodulator for treating TB.

GM-CSF and IL-7 fusion cytokine engineered tumor vaccine generates long-term Th-17 memory cells and increases overall survival in aged syngeneic mouse models of glioblastoma.

Age-related immune dysfunctions, such as decreased T-cell output, are closely related to pathologies like cancers and lack of vaccine efficacy among the elderly. Engineered fusokine, GIFT-7, a fusion of interleukin 7 (IL-7) and GM-CSF, can reverse aging-related lymphoid organ atrophy. We generated a GIFT-7 fusokine tumor vaccine and employed it in aged syngeneic mouse models of glioblastoma and found that peripheral vaccination with GIFT-7TVax resulted in thymic regeneration and generated durable long-term antitumor immunity specifically in aged mice. Global cytokine analysis showed increased pro-inflammatory cytokines including IL-1β in the vaccinated group that resulted in hyperactivation of dendritic cells. In addition, GIFT-7 vaccination resulted in increased T-cell trafficking to the brain and robust Th-17 long-term effector memory T-cell formation. TCR-seq analysis showed increased productive frequency among detected rearrangements within the vaccinated group. Overall, our data demonstrate that aging immune system can be therapeutically augmented to generate lasting antitumor immunity.

The generation of stem cell-like memory cells early after BNT162b2 vaccination is associated with durability of memory CD8+ Tcell responses.

COVID-19 vaccines elicit humoral and cellular immune responses. Durable maintenance of vaccine-induced immunity is required for long-term protection of the host. Here, we examine activation and differentiation of vaccine-induced CD8+ T cells using MHC class I (MHC-I) multimers and correlations between early differentiation and the durability of CD8+ T cell responses among healthcare workers immunized with two doses of BNT162b2. The frequency of MHC-I multimer+ cells is robustly increased by BNT162b2 but decreases 6 months post-second vaccination to 2.4%–65.6% (23.0% on average) of the peak. MHC-I multimer+ cells dominantly exhibit phenotypes of activated effector cells 1–2 weeks post-second vaccination and gradually acquire phenotypes of long-term memory cells, including stem cell-like memory T (TSCM) cells. Importantly, the frequency of TSCM cells 1–2 weeks post-second vaccination significantly correlates with the 6-month durability of CD8+ T cells, indicating that early generation of TSCM cells determines the longevity of vaccine-induced memory CD8+ T cell responses.

Neural network technologies for analysis and risk assessment in forecasting the market of industrial financial instruments

The issues of risk analysis and assessment in forecasting the dynamics of prices on the stock exchange and the OTC market have always been a difficult task for many researchers and analysts. Successful investment is largely determined by knowledge of the future situation in the financial market. The article deals with the issues of search and development of technical tools for risk analysis and assessment in forecasting the market of derivative financial instruments under conditions of uncertainty. A recurrent network with a long-term short-term memory cell LSTM, which is one of the most powerful prediction models, was chosen as the architecture of neural networks. The development of technical tools for solving this problem was carried out on the basis of the C# programming language. An additional TA-Lib library served as a mathematical base for technical analysis, from which 42 technical analysis indicators were used during the development process, and for working with the LSTM recurrent network, the library Keras.NET. The ability to efficiently link memory and input remote data using these network memory cells provides a dynamic understanding of the data structure over time. The estimates of the accuracy of the forecast for the cost indicators of a derivative financial instrument obtained as a result of computer experiments showed the high efficiency of the constructed neural network model.

A high-performance neural network vehicle dynamics model for trajectory tracking control

Traditional models of vehicle dynamics engineered from physical principles are usually simplified and assumed, resulting in the model cannot accurately reflect the actual dynamic characteristics of the vehicle under some working conditions, affecting the control accuracy and even safety. In view of this, inspired by the single-track model, this paper uses the data-driven methods to establish a new high-performance time-delay feedback neural network vehicle dynamics model. The feedback connection of a network can describe complex dynamics. The multi-time-step input of the state and control can include highly nonlinear and strong coupling characteristics of a vehicle. The test results of modeling accuracy show that the proposed model can achieve higher vehicle dynamics prediction accuracy than nonlinear vehicle model. Different from the traditional vehicle dynamics model, the proposed model has long-term memory cells, which can implicitly predict coefficient of friction and can be applied to different road conditions. Then, the trajectory tracking control algorithm is designed based on the proposed vehicle model. According to the steady-state steering assumption, the feedforward front wheel steering angle is calculated, and the steady-state sideslip angle is integrated into the steering feedback according to the reference path to realize the reference trajectory tracking control. Finally, Simulink/CarSim is used to conduct the simulation analysis under the double lane change conditions to evaluate the proposed control algorithm. The analysis results show that the control algorithm based on the proposed model can achieve an accurate tracking control effect of a vehicle at medium and high speeds, providing high-accuracy track tracking and good lateral stability of intelligent vehicles.

Allergic airway recall responses require IL-9 from resident memory CD4+ T cells.

Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses is not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we characterized a subpopulation of CD4+ T cells that secreted IL-9 as an obligate effector cytokine. IL-9-secreting cells had a resident memory T cell phenotype, and blocking IL-9 during a recall challenge or deleting IL-9 from T cells significantly diminished airway inflammation and airway hyperreactivity. T cells secreted IL-9 in an allergen recall-specific manner, and secretion was amplified by IL-33. Using scRNA-seq and scATAC-seq, we defined the cellular identity of a distinct population of T cells with a proallergic cytokine pattern. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multicytokine-producing CD4+ T cell population was required for an allergen recall response.

Player Behavior Modeling for Enhancing Role-Playing Game Engagement

Role-playing games (RPGs) are one of the most exciting and most rapidly expanding genres of online games. Virtual characters that are not controlled by players, have become an integral part, which helps to advance narratives of RPGs. Believable characters can enhance game engagement and further improve player retention. However, game players easily find that most characters' behaviors are limited and improbable, resulting in a less meaningful game experience. In this work, we propose a framework to model game behaviors to learn behavior patterns of human players. Based on the learned behavior patterns, it generates human-like action sequences that can be used for the design of believable virtual characters in RPGs, so as to enhance game engagement. Specifically, considering the influence of game context in behavior patterns, we integrate game context (players' levels and game classes) with actions together to model behaviors. We propose a long-term memory cell on actions and game context to learn the hidden representations. We also introduce an attention mechanism to measure the contribution of the actions previously performed to the next action. Given only one action, our model can generate action sequences by predicting the succeeding action based on the previously generated actions. The model was evaluated on a real-world data set of over 22 000 players and more than 51 million action logs of an RPG game in 21 days. The results demonstrate the state-of-the-art performance.

The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome

AbstractCancer immunotherapy is advancing rapidly and gene-modified T cells expressing chimeric antigen receptors (CARs) show particular promise. A challenge of CAR-T cell therapy is that the ex vivo–generated CAR-T cells become exhausted during expansion in culture, and do not persist when transferred back to patients. It has become clear that naive and memory CD8 T cells perform better than the total CD8 T-cell populations in CAR-T immunotherapy because of better expansion, antitumor activity, and persistence, which are necessary features for therapeutic success and prevention of disease relapse. However, memory CAR-T cells are rarely used in the clinic due to generation challenges. We previously reported that mouse CD8 T cells cultured with the S enantiomer of the immunometabolite 2-hydroxyglutarate (S-2HG) exhibit enhanced antitumor activity. Here, we show that clinical-grade human donor CAR-T cells can be generated from naive precursors after culture with S-2HG. S-2HG–treated CAR-T cells establish long-term memory cells in vivo and show superior antitumor responses when compared with CAR-T cells generated with standard clinical protocols. This study provides the basis for a phase 1 clinical trial evaluating the activity of S-2HG–treated CD19-CAR-T cells in patients with B-cell malignancies.

Dipeptide IF prevents the effects of hypertension-induced Alzheimer's disease on long-term memory in the cortex of spontaneously hypertensive rats.

Hypertension (HTN) is one of the most prevalent chronic conditions; it can damage blood vessels and rupture blood vessels can trap in small vessels. This blockage can prevent blood flow and oxygen delivery to brain cells and can result in Alzheimer's disease (AD). HTN- and AD-mediated long-time memory loss and its treatment remain poorly understood. Plant-derived natural compounds are alternative solutions for effectively treating diseases without any side effects. This study revealed that bioactive peptides extracted from potato hydrolysis suppress HTN-mediated long-term memory (LTM) loss and cell apoptosis, thus improving memory formation and neuronal cell survival in the spontaneously hypertensive rat (SHR) rat model. SHR rats were treated with bioactive peptide IF (10 mg/kg orally) and angiotensin-converting enzyme inhibitors (5 mg/kg orally). In this study, we evaluated the molecular expression levels of BDNF-, GluR1-, and CREB-mediated markers protein expression in 24-week-old SHR rats. The study result showed that HTN-induced AD regulated long-term memory (LTM) loss and neuronal degeneration in the SHR animals. The bioactive peptide-treated animals showed an elevated level of survival proteins. Bioactive peptide IF activate CREB-mediated downstream proteins to regulate synaptic plasticity and neuronal survival in the SHR rat model.

Phenotype and specificity of T cells in primary human cytomegalovirus infection during pregnancy: IL-7Rpos long-term memory phenotype is associated with protection from vertical transmission.

Congenital human cytomegalovirus (HCMV) infection is the major cause of birth defects and a precise definition of the HCMV-specific T-cell response in primary infection may help define reliable correlates of immune protection during pregnancy. In this study, a high throughput method was used to define the frequency of CD4+ and CD8+ T cells specific for four HCMV proteins in the naïve compartment of seronegative subjects and the effector/memory compartments of subjects with primary/remote HCMV infection. The naïve repertoire displayed comparable frequencies of T cells that were reactive with HCMV structural (pp65, gB and the pentamer gHgLpUL128L) and non-structural (IE-1) proteins. Whereas, following natural infection, the majority of effector/memory CD4+ and CD8+ T cells recognized either gB or IE-1, respectively, and pp65. The pattern of T cell reactivity was comparable at early and late stages of infection and in pregnant women with primary HCMV infection transmitting or not transmitting the virus to the fetus. At an early stage of primary infection, about 50% of HCMV-reactive CD4+ T cells were long-term IL-7Rpos memory cells, while 6–12 months later, the frequency of these cells increased to 70%, approaching 100% in remote infections. In contrast, only 10–20% of HCMV-specific CD8+ T cells were long-term memory cells up to 12 months after infection onset, thereafter increasing to 70% in remote infections. Interestingly, a significantly higher frequency of HCMV-specific CD4+ T cells with a long-term IL-7Rpos memory phenotype was observed in non-transmitting compared to transmitting women. These findings indicate that immunodominance in HCMV infection is not predetermined in the naïve compartment, but is the result of virus-host interactions and suggest that prompt control of HCMV infection in pregnancy is associated with the rapid development of long-term IL-7Rpos memory HCMV-specific CD4+ T cells and a low risk of virus transmission to the fetus.

Identification of Nascent Memory CD8 T Cells and Modeling of Their Ontogeny

Primary immune responses generate short-term effectors and long-term protective memory cells. The delineation of the genealogy linking naive, effector, and memory cells has been complicated by the lack of phenotypes discriminating effector from memory differentiation stages. Using transcriptomics and phenotypic analyses, we identify Bcl2 and Mki67 as a marker combination that enables the tracking of nascent memory cells within the effector phase. We then use a formal approach based on mathematical models describing the dynamics of population size evolution to test potential progeny links and demonstrate that most cells follow a linear naive→early effector→late effector→memory pathway. Moreover, our mathematical model allows long-term prediction of memory cell numbers from a few early experimental measurements. Our work thus provides a phenotypic means to identify effector and memory cells, as well as a mathematical framework to investigate their genealogy and to predict the outcome ofimmunization regimens in terms of memory cell numbers generated.

Local Cellular and Cytokine Cues in the Spleen Regulate In Situ T Cell Receptor Affinity, Function, and Fate of CD8+ T Cells

T cells rapidly undergo contraction upon viral clearance, but how Tcell function and fate are determined during this phase is unclear. During the contraction phase of an acute infection with lymphocytic choriomeningitis virus, we found that virus-specific CD8+ Tcells within the splenic red pulp (RP) had higher two-dimensional (2D) effective affinity than those within the white pulp (WP). This increased antigen recognition of RP-derived CD8+ Tcells correlated with more efficient target cell killing and improved control of viremia. FoxP3+ regulatory Tcells and cytokine TGF-β limited the 2D-affinity in the WP during the contraction phase. Anatomical location drove gene expression patterns in CD8+ Tcells that led to preferential differentiation of memory precursor WP Tcells into long-term memory cells. These results highlight that intricate regulation of Tcell function and fate is determined by anatomic compartmentalization during the early immune contraction phase.

CD4+ T Follicular Helper and IgA+ B Cell Numbers in Gut Biopsies from HIV-Infected Subjects on Antiretroviral Therapy Are Similar to HIV-Uninfected Individuals.

Disruption of gastrointestinal tract epithelial and immune barriers contribute to microbial translocation, systemic inflammation, and progression of HIV-1 infection. Antiretroviral therapy (ART) may lead to reconstitution of CD4+ T cells in gut-associated lymphoid tissue (GALT), but its impact on humoral immunity within GALT is unclear. Therefore, we studied CD4+ subsets, including T follicular helper cells (Tfh), as well as resident B cells that have switched to IgA production, in gut biopsies, from HIV+ subjects on suppressive ART compared to HIV-negative controls (HNC). Twenty-three HIV+ subjects on ART and 22 HNC undergoing colonoscopy were recruited to the study. Single-cell suspensions were prepared from biopsies from left colon (LC), right colon (RC), and terminal ileum (TI). T and B lymphocyte subsets, as well as EpCAM+ epithelial cells, were accurately enumerated by flow cytometry, using counting beads. No significant differences in the number of recovered epithelial cells were observed between the two subject groups. However, the median TI CD4+ T cell count/106 epithelial cells was 2.4-fold lower in HIV+ subjects versus HNC (19,679 versus 47,504 cells; p = 0.02). Similarly, median LC CD4+ T cell counts were reduced in HIV+ subjects (8,358 versus 18,577; p = 0.03) but were not reduced in RC. Importantly, we found no significant differences in Tfh or IgA+ B cell counts at either site between HIV+ subjects and HNC. Further analysis showed no difference in CD4+, Tfh, or IgA+ B cell counts between subjects who commenced ART in primary compared to chronic HIV-1 infection. Despite the decrease in total CD4 T cells, we could not identify a selective decrease of other key subsets of CD4+ T cells, including CCR5+ cells, CD127+ long-term memory cells, CD103+ tissue-resident cells, or CD161+ cells (surrogate marker for Th17), but there was a slight increase in the proportion of T regulatory cells. While there were lower absolute CD4+ counts in the TI and LC in HIV+ subjects on ART, they were not associated with significantly reduced Tfh cell counts or IgA+ B cells, suggesting that this important vanguard of adaptive immune defense against luminal microbial products is normalized following ART.

An In Vitro Model That Predicts the Therapeutic Efficacy of Immunomodulatory Antibodies.

Immunomodulatory monoclonal antibodies (mAbs) have efficacy in patients with advanced cancer and are the focus of intensive research. However, cures are infrequent and responses vary among tumor types and among subjects with the same tumor. An in vitro test would be valuable to determine the most effective mAb combination for a given case and to evaluate novel agents. Toward this goal, we investigated the ability of various mAb combinations to generate a tumor-destructive immune response in vitro in the presence of lymphoid cells from mice with established TC1 lung carcinoma, B16 melanoma, or SW1 melanoma. The data strongly correlate (r=0.9, 0.89, and 0.91, respectively) with the therapeutic efficacy of the respective mAb combinations. Both in vivo and in vitro, tumor destruction was associated with a shift from a Th2 to a Th1 response and included a dramatic increase of long-term memory cells. A combination of mAbs to CD137/PD-1/CTLA4/CD19 was most efficacious.

Anatomic partitioning regulates TCR-pMHC interaction and memory T cell development during early immune contraction phase

Abstract As virus is cleared, immune cells rapidly undergo contraction; however, how cell function and fate are determined during this phase is not yet fully understood. We unexpectedly discovered that during the early immune contraction phase of an acute infection with lymphocytic choriomeningitis virus, the two dimensional TCR–pMHC effective affinity of TCR transgenic P14 T cells was significantly higher for cells from the splenic red pulp (RP) than the white pulp (WP) compartment. This difference in seeing antigen was governed by FoxP3+ regulatory T cells and TGF-beta. Further, memory precursors from WP preferentially developed into long-term memory cells as compared to cells from RP, despite expression of identical cell surface markers. Our results highlight that intricate regulation of T cell function and fate is determined by anatomic partitioning during the early immune contraction phase. These findings could have an important impact on development of more efficient vaccines and T cell-targeted immunotherapy for infectious diseases, cancers, and autoimmune disorders.

Anatomic Compartmentalization Regulates TCR-PEP-MHC Interaction and Fate

Whether anatomic location affects T cell function and differentiation has not been defined. Unexpectedly we found, during the early contraction phase of an acute resolving infection with lymphocytic choriomeningitis virus (LCMV) Armstrong, antigen-specific TCR transgenic P14 T cells within the splenic red pulp displayed a higher number of TCR-pMHC bonds (higher affinity) than those from the white pulp when measured by 2D micropipette adhesion frequency assay. This increased bond formation correlated with target cell killing by P14 T cells. Importantly, FoxP3+ regulatory T cells and TGF-β were required to maintain steady levels of TCR-pMHC interactions in the white pulp. Furthermore, memory precursors from the white pulp preferentially developed into long-term memory cells. Our findings highlight anatomic location as a critical regulator of fate and function.

Abstract LB-227: Novel synthetic vesicle for rapid in vivo expansion of CD8 T cells can significantly improve checkpoint inhibitor therapy

Abstract Harnessing the immune system for cancer treatment offers many advantages over traditional methods as the immune system can generate tumor-specific killer cells and long-term memory cells to prevent recurrence. The success of recent clinical trials using T cell therapies has proven the potential of immunotherapy, but the ex vivo generation of T cells in these trials is costly and labor-intensive. Here, we developed wholly synthetic, pathogen-mimicking nanocapsules, Interbilayer-Crosslinked Multilamellar Vesicles (ICMVs), to deliver antigens to the lymphoid system, which prime large tumor-specific CD8 T cell populations in vivo. ICMVs use bilayer-to-bilayer crosslinks in the walls of multi-lamellar lipid vesicles to create an easily manufacturable, highly stable virus-like particle to present antigens and/or adjuvants to immune cells. ICMV carrying HPV16 E6 and E7 full-length proteins were administered alone or co-encapsulated with TLR agonists to mice. CD8 T cell responses were assessed by tetramer staining and intracellular cytokine staining (ICS) was done to assay functionality. Efficacy of ICMV treatment was demonstrated by monitoring tumor size and survival in C57BL/6 mice bearing a lethal dose of TC-1 tumor cells. ICMVs induced unprecedented antigen-specific CD8 T cell frequencies against HPV whole proteins even without added adjuvant. Repeat doses of ICMVs boosted CD8 responses resulting in 30% of the total CD8 T cell population in blood being E7-specific while treatment with free protein elicited <1% E7-specific cells, indicating that ICMVs promote strong cross-presentation of antigens. When ICMVs were combined with anti-PD-1 to treat tumor-bearing mice, 10-15% of CD8 T cells produced IFNγ+ in response to either E6 or E7 antigens, while treatment with anti-PD-1 alone elicited <1% IFNγ+ T cells. Significant tumor regression was seen with ICMV+anti-PD-1 treatment, doubling overall survival time while anti-PD-1 treatment alone delayed tumor growth only slightly. Similar results were seen when ICMV were combined with various immunomodulators including anti-PD-L1, anti-CTLA-4 and anti-CD40. These results indicate that the ICMV-induced expansion of antigen-specific CD8 T cells can significantly improve the therapeutic efficacy of checkpoint inhibitors. A triple therapy of ICMV + checkpoint inhibitor + Treg inhibiting drugs is now being assessed and eradication of >85% of established tumors was detected in preliminary experiments. These findings demonstrate the potential of ICMVs as a novel cancer immunotherapy platform for the in vivo generation of CD8 T cells. ICMV are a cost effective, easily manufactured and versatile strategy to generate T cells for immunotherapy. Citation Format: Adrienne V. Li, Jackson K. Eby, Peter C. DeMuth, Darrell J. Irvine. Novel synthetic vesicle for rapid in vivo expansion of CD8 T cells can significantly improve checkpoint inhibitor therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-227. doi:10.1158/1538-7445.AM2015-LB-227

Phenotype and function of protective, CD4-independent CD8 T cell memory

While the need for CD4 T cells in the generation of CD8 T cell memory has been well documented, the mechanism underlying their requirement remains unknown. Here, we detail an immunization method capable of generating CD8 memory T cells that are indifferent to CD4 T cell help. Using a subunit vaccination that combines polyIC and an agonistic CD40 antibody, we program protective CD4-independent CD8 T cell memory. When cells generated by combined polyIC/CD40 immunization are compared to cells produced following a CD4-dependent vaccination, Listeria monocytogenes, they display dramatic differences, both phenotypically and functionally. The memory cells generated in a CD4-deficient host by polyIC/CD40 immunization provide protection against secondary infectious challenge, whereas cells generated by LM immunization in the same environment do not. Interestingly, combined polyIC/CD40 immunization generates long-term memory cells with low Blimp-1 and elevated Eomes expression despite high expression of Blimp-1 during the primary response. The potency of combined polyIC/CD40 to elicit CD8+ T cell memory in the absence of CD4 T cells suggests that it could be considered as a vaccine adjuvant in clinical situations where CD4 responses/numbers are compromised.

T‐follicular helper cells survive as long‐term memory cells

T-follicular helper (TFH) cells represent the subpopulation of CD4(+) T cells that provides help for antigen-specific B cells in the GC response. They are generated from naïve T cells during an immune response and are imprinted by their master transcription factor Bcl-6. It has been a long-standing question if TFH cells contribute to the CD4(+) memory pool after the GC response has been terminated. To answer this question, we sorted antigen-specific TFH and non-TFH effector cells from an ongoing GC response and transferred them into naïve mice. Without further signals via the TCR, transferred cells rapidly contracted with a small population of both TFH and non-TFH cells surviving as memory cells in peripheral lymphoid organs for at least 4 weeks in the absence of antigen. TFH cells strongly downregulated their signature genes Bcl-6, CXCR5, and PD-1 in the memory phase. Upon rechallenge with antigen they rapidly upregulated these markers again. An enhanced potential to produce IL-21, paired with higher expression of CXCR5 and lower expression of CCR7, should enable TFH memory cells to provide more efficient help for antigen-specific B cells than their non-TFH counterparts.