Memory Responses Research Articles

Microanatomical lipid niche controls intestinal memory B cell migration and effector function

Abstract Enteric infections are a leading global burden, yet few oral vaccines elicit long-lasting immunity and prevent disease, likely due to our lack of understanding of intestinal immunological memory. Long-lived memory B cells can be rapidly reactivated to differentiate into plasma cells, thus further increasing antibody titers and mediating host protection. Such long-term protection requires memory B cells to migrate and persist in sub-anatomical niches within secondary lymphoid organs. While survival niches have been described for memory B cells in lymph nodes and spleen, no niche have been identified in mucosal lymphoid organs, such as Peyer’s patches (PPs). Here, we show that memory B cells require positioning in the PP subepithelial dome (SED) for maintenance and effector function. In PPs, memory B cells express the migratory receptors EBI2, which binds the oxysterol 7alpha, 25-hydroxycholesterol, and CCR6, which recognizes the chemokine CCL20. Both ligands are present in PPs and drive memory B cell migration in vitro. Conditional removal of EBI2 from memory B cells, either in a constitutive or acute fashion, alters their zonation in PPs, reduces their persistency, and impairs their antigen-specific response. While most memory B cells in PPs are IgA+, IgA B cell receptor expression is dispensable for memory B cell positioning in the SED. Using conditional mice for the enzymes generating the oxysterol gradient and cell specific Cre lines, we are currently mapping the cellular and metabolic requirements for EBI2 dependent memory B cell maintenance and effector function in PPs. Understanding the mechanisms for memory B cell persistence is fundamental to our understanding of the intestinal B cell memory response against pathogens. Previously supported by training grants from NIH (5 T32 AI 132152-2, 5 T32 AI 007349-29)

Iron-overload affects anti-tumor immune response in pancreatic cancer.

Abstract HFE is the most frequently mutated gene in hereditary hemochromatosis, a disease in which iron accumulates in organs leading to toxicities. Worldwide, two main polymorphisms in HFE protein have been observed, namely C282Y and H63D. Even if associated to milder iron accumulations, H63D polymorphism increases the risk of cancer development and aggressiveness. As observed in pancreatic cancer patients, a great percentage of those that underwent to surgery also present H63D polymorphism but displayed a worse survival. To better characterize how the iron accumulation affects anti-tumor response in the context of the pancreatic ductal adenocarcinoma (PDA), we crossed genetically engineered mice (GEM) that spontaneously develop PDA with mice engineered to express H67D mutation (HfeH67D), the orthologue of H63D in human. Histological analysis of GEM showed that H67D polymorphism accelerated PDA progression, increased the number of metastases, and altered the composition of infiltrating immune cells. Accordingly, these mouse models also displayed a reduced overall survival compared to controls. By exploiting OVA as a well-known antigen, we injected OVA-expressing PDA cells subcutaneously in mice carrying or not the H67D mutation to assess their ability to mount a normal memory response. OVA-expressing PDA cells grew faster in the presence of H67D polymorphism, but immunized mice displayed a reduction in tumor volume similar to the WT counterpart. HfeH67Dmice displayed an increased production of anti-OVA IgG antibodies, especially IgE, but a decreased in OVA-specific IFNγ-secreting T cells. Overall, H67D polymorphism impacts the activation of anti-tumoral immune response, which consequently worsens PDA progression. Supported by grants from AIRC (ID22234; ID26341)

Characterization, functional validation, and analysis of the cross-reactive T cell repertoire in the context of heterosubtypic influenza A virus infection

Abstract The T cell receptor (TCR) repertoire is extremely diverse and plays an instrumental role in fighting off pathogens individuals encounter in a lifetime. A key aspect of the immune system combatting the diverse array of pathogens an individual sees may be TCR cross-reactivity, where a TCR can recognize more than one peptide displayed on an MHC-I molecule. Specifically, cross-reactive TCRs may play a key role in allowing the immune system to adapt to rapidly evolving pathogens, such as influenza A virus (IAV). Utilizing 6 variant influenza viruses for priming and secondary challenge, our preliminary data has shown that cross-reactive TCRs seen in primary infection with one IAV can mount a robust and effective memory response to a different IAV, across a range of mutations. However, selection for cross-reactive receptors over multiple infections may create a narrowed repertoire consisting of a few clonotypes, covering a narrow range of antigenic space representing the mutant epitopes encountered. Our data shows that cross-reactive TCRs are more similar to each other than single epitope specific cells and that cross-reactivity can be replicated during peptide stimulation when cross-reactive TCRs are transduced into TCR null cell lines invitro. Given the narrowing nature of cross-reactive responses elicited over different infections, selection for cross-reactivity may provide a substantial escape opportunity with future antigenic variations. Ongoing work focuses on how repeated IAV challenges shape the repertoire, and how previous infections inform future responses by selected cross-reactive T cell pools. Supported by NIH Grant R01112404040 and the St. Jude Graduate School of Biomedical Sciences

Metformin treatment of CD8 T cells decreases pro-inflammatory cytokine production and shifts their metabolic state toward oxidative metabolism

Abstract Obesity is a systemic metabolic disorder that affects over 40% of the U.S. adult population. Among many other serious health consequences, obesity leads to increased morbidity and mortality from select infections and impaired immunological memory responses to these infections. CD8 T cells mediate the clearance of pathogens and establish immunological memory. Many studies have established that T cell metabolism and function are linked, and that changes in T cell metabolism can alter T cell responses; however, it is currently unknown how obesity impacts CD8 T cell metabolism and their ability to respond to pathogens. Furthermore, it is also unknown if drugs used to reverse the metabolic effects of obesity can alter CD8 T cell metabolism and impact CD8 T cell response to infection. To test this, we first isolated splenic CD8 T cells from lean or diet-induced obese (DIO) mice, activated them in the presence or absence of the drug metformin, and measured T cell function and metabolism using flow cytometry and extracellular flux analysis. CD8 T cells activated in the presence of metformin showed significantly decreased production of IFN-γ and Granzyme B and decreased oxidative metabolism. To note, we saw a similar decrease in oxidative metabolism in splenic CD8 T cells isolated from DIO mice that were treated with metformin systemically for six weeks. These results demonstrate that metformin treatment either in vitroor in vivoaffects CD8 T cell metabolism and function. To determine if metformin treatment improves immunological memory in the context of infectious diseases, future studies will include immunological analyses of CD8 T cells from lungs of influenza virus-infected lean and DIO mice that have been treated with out without metformin. Supported by grants from NIH (R01-DK106090)

PI3Kdelta coordinates transcriptional, epigenetic and metabolic changes to promote effector CD8 T cells differentiation.

Abstract Activated PI3K-delta syndrome (APDS) is a primary immunodeficiency caused by heterozygous activating mutations of PIK3CD, resulting in dysregulated immunity, recurrent infections and lymphoproliferation, yet underlying mechanisms behind these phenotypes remain unclear. Using patient samples and Pik3cd E1020K/+mouse model, we evaluated CD8 cell function both in vitro and in response to infectious agents, assessing cellular phenotypes, metabolism, gene expression and chromatin organization. Pik3cd E1020K/+CD8 cells exhibited accelerated differentiation to short-lived effectors, associated with increased mTORC1 and c-Myc pathways, as well as altered metabolic, transcriptional and epigenetic circuits characterized by a pronounced IL-2/STAT5 signature associated with heightened IL-2 responses that prevented IL-15 differentiation to memory-like cells. Moreover, Pik3cd E1020K/+CD8 cells failed to sustain expression of proteins critical for maintenance of long-lived memory cells, including TCF1, and mounted inadequate central memory responses in vivo with enhanced generation of long-lived effector populations. In response to chronic LCMV Clone 13 infection, Pik3cd E1020K/+mice rapidly die, yet the surviving mice recover more rapidly than WT counterparts. Pik3cd E1020K/+mice fail to sustain TCF1 +Ly108 +stem-like CD8 cells, with a simultaneous reduction in exhausted cells. However, Pik3cd E1020K/+mice also have an expansion of CX3CR1 +effector cells associated with increased viral clearance and increased immunopathology. Our data position PI3Kd as a central hub integrating multiple signaling nodes that promote an accelerated effector T cell program during both acute and chronic infections. This work was supported by the Intramural Research Program of NIAID and NHGRI, NIH.

The nature of the stimulant differentially impacts the innate memory response of monocytes to Mycobacterium tuberculosis

Abstract Innate immune cells, such as monocytes, can generate a non-specific ‘memory’ response (a.k.a. trained immunity) upon stimulation with an antigen/bacterium (e.g., LPS or BCG), which confers heterologous protection against another infectious agent. However, the association between the nature of stimulants and the corresponding immune correlate of trained immunity is not fully understood. Similarly, the response of macrophages “trained” by various stimulants to subsequent infection by different clinical Mycobacterium tuberculosis(Mtb) strains remains unknown. Here, we report the trained immunity profile of the blood-derived monocytes (BDM) of BCG-vaccinated adults and monocytic THP-1 cells after stimulation with BCG, LPS, Purified Protein Derivative (PPD), heat-killed MtbHN878 or MtbCDC1551 strains. The response of monocytes trained by these agents to subsequent infection with clinical Mtb isolates HN878 and CDC1551, which differ in their virulence potential, was evaluated using standard molecular and cellular immunologic assays. The BCG- and LPS-trained macrophages produced higher proinflammatory, antimicrobial responses, and autophagy induction than unstimulated, PPD, HK-HN878, or CDC1551-stimulated cells. The HN878-infected trained THP-1 cells elicited a more robust inflammatory response than the CDC1551 infection. A significantly reduced intracellular Mtb growth was noted in the BCG and LPS-trained THP-1 cells, which was augmented by adding rapamycin, an autophagy inducer. A similar immunological response was noted in the BDM of BCG-vaccinated adults infected with these Mtb strains. Thus, the nature of the stimulant affects the macrophages’ trained immunity profile and its response to Mtb infection. Supported by grants from NIH (R01 AI161822) and the Bill and Melinda Gates Foundation (INV-009099; formerly OPP1157210).

Mechanistic investigations of granzyme A adjuvant effects on γ 9δ 2T cells

Abstract γδ T cells are ideal effector cells against cancer and pathogens for numerous reasons: they are found in blood, mucosa, and lymphoid organs, develop memory responses independent of MHC restriction, present antigen, produce cytokines, and are cytolytic. An obstacle for the development of biomedical interventions targeting γδ T cells is the need for an adjuvant that promotes their expansion and is suitable for human use. The adjuvant routinely used, IL-2, has multiple drawbacks limiting its use for vaccination. Our lab has shown that memory γ 9δ 2T cells, induced by BCG vaccination, are expanded in vitro by M. tuberculosis, M.bovis(BCG), and our lab’s vaccine candidate 6-O-methylglucoselipopolysaccharide (mGLP), in the presence of IL-2. Additionally, the expanded γ 9δ 2T cells inhibit intracellular mycobacterial growth. This inhibition is dependent on granzyme A (GzmA) production by γ 9δ 2T cells, and GzmA alone can inhibit intracellular mycobacterial growth. We recently identified that GzmA can also promote expansion of γδ T cells, without exogenous IL-2, in response to mGLP and HMBPP, a phosphoantigen that stimulates all γ 9δ 2T cells. To identify γδ T cell adjuvants, in vitro expansion assays were performed using human peripheral blood mononuclear cells, dendritic cells, antigen, and adjuvant. The absolute numbers of expanded effector γδ T cells were calculated using flow cytometry after 7 days of culture. We identified that the ability of GzmA to promote γδ T cell expansion is dependent upon TLR4, CD14, and GzmA homodimerization, but independent of GzmA enzymatic activity. This new information has broad implications for vaccine design, promoting γδ T cell responses, and understanding the role of GzmA in infectious disease and cancer. Supported by grants from NIH (R01 AI048391) and Bill & Melinda Gates Foundation (OP1118659)

Cryoablation inhibits the recurrence and progression of bladder cancer by enhancing tumour‐specific immunity

Recurrence and metastasis of bladder cancer are major factors affecting patient prognosis. Endoscopic cryoablation achieved a better clinical outcome among clinical patients and could be synergistic with ICIs. Thus, this study aimed to evaluate the immunological mechanism of cryoablation for bladder cancer to reveal the therapeutic mechanism. We systematically reviewed the clinical prognosis of patients underwent cryoablation at Huashan Hospital in these first-in-human studies (ChiCTR-INR-17013060). Murine models were constructed to explore cryoablation-induced tumour-specific immunity, which was further confirmed by primary bladder tumour organoids and autologous lymphocytes cocultured system. Cryoablation improved progression-free survival and recurrence-free survival respectively. Assessment of murine models after cryoablation confirmed microenvironment remodelling and tumour-specific T cells expansion. Enhanced antitumour effects were found after coculture of organoids with autologous lymphocytes collected from post-cryoablation. We also demonstrated cryoablation-induced tumour elimination required IFNGR expression on tumour cells. In addition, a long-lasting antitumour memory response is achieved by cryoablation and could be enhanced after combination with ICIs. This study revealed endoscopic cryoablation is an efficient and safe therapy for bladder tumour treatment. The tumour-specific immune responses induced by cryoablation could reduce tumour recurrence and metastasis.

Nontypeable Haemophilus influenzaespecific memory T H17 cells protect against secondary bacterial pneumonia following Influenza A virus infection

Abstract Nontypeable Haemophilus influenzae(NTHi) is one of the most common bacteria that cause secondary bacterial pneumonia following influenza A virus (IAV) infection, leading to hospitalization and death associated with IAV infection worldwide. Current efforts to develop vaccines against NTHi infection focus on inducing antibodies but are hindered by antigenic diversity among NTHi strains. Therefore, we interrogated the contribution of the memory T-helper type 17 (T H17) response in protective immunity against IAV/NTHi co-infection. We observed that co-infected mice exhibited prolonged NTHi infection in the lungs even at mild IAV infection and impaired NTHi-specific T H17 responses compared to NTHi mono-infected mice. However, immune mice that recovered from a prior NTHi infection were protected from homologous and heterologous secondary NTHi strains following IAV infection. Our data further revealed that memory NTHi-specific T H17 cells overcame IAV-driven impairments of anti-NTHi T H17 responses and were cross-reactive with different NTHi strains. Last, mice immunized with a NTHi protein that induced a strong T H17 memory response were broadly protected against diverse NTHi strains following challenge with IAV/NTHi co-infection. These results indicate that NTHi-specific memory T H17 cells are capable of providing serotype-independent protection against co-infection and demonstrate the advantage of developing broadly protective T H17-inducing vaccines against secondary bacterial pneumonia.

Vaccine antigen archiving by lymphatic endothelial cells boosts archived antigen-specific CD8 T cell memory responses during a pathogenic challenge

Abstract Numerous studies have shown viral antigens can persist in lymph nodes after the resolution of the infection. We demonstrated that lymphatic endothelial cells (LEC), which comprise the lymphatic vasculature necessary for antigen drainage from the tissue, are the predominant cell type required for the persistence of both vaccine and viral antigens within the lymph node. We termed this process antigen archiving due to the ability of LEC to actively archive antigens to which an immune response has occurred. This process involves antigen acquisition, retention, and exchange of the antigen between LECs and dendritic cells (DC), resulting in the presentation of the archived antigens to archived antigen-specific CD8 memory T cells. In this study, we evaluated the effect of LEC archived antigen on archived antigen-specific memory T cells during a pathogenic challenge. We predicted that a pathogenic challenge would result in the release of the archived antigen and subsequent archived antigen presentation. Following a pathogenic challenge, we found a significant increase in archived antigen-specific endogenous or transferred memory CD8 T cells, compared to bystander activation seen by memory T cells of an unrelated specificity. The phenotype of the archived antigen-specific memory CD8 T cells was more effector-like and led to a significant increase in protection against Listeria monocytogenes (LM)-expressing the archived antigen, in the local area. In conclusion, these findings suggest that archived antigen may be released during a pathogenic challenge. As such, the archived antigen may be acquired by migratory DCs as they traffic through the lymphatics in order to present the archived antigen to memory CD8 T cells acting as an effective boost. NIH R01 AI121209

Normalizing pathogen exposure via pet shop mouse cohousing leads to preferential maintenance of long-lived effector memory CD8 T cells

Abstract Studies of the CD8 T cell memory compartment in mice have primarily been done in young mice maintained in specific pathogen free (SPF) environment. The murine compartment is skewed towards central memory CD8 T cells, whereas adult human memory T cells are dominated by effector memory T cells. The murine memory compartment is akin to that of neonate humans, suggesting there are factors missing in SPF mice that are required to mature the T cell compartment. We wanted to ask how pathogen exposure changes the memory compartment of mice, so we utilized a model of pet shop mouse co-housing (COH), which exposes mice to a wide variety of normal mouse pathogens. COH mice display a substantial increase in long-lived effector CD8 T cells (LLEC). LLEC are a CD8 T cell memory population described by the Hamilton Lab that is phenotypically more effector-like and are highly effective at clearing systemic infections when compared to other memory T cells. However, LLEC display reduced homeostatic and antigen-driven proliferation in SPF mice leading to a lower representation in the memory pool. The factors in COH that support LLEC expansion and persistence are currently unknown, and it is also unclear if COH impacts LLEC function. Thus, the goal of this study is to understand what intrinsic and environmental factors contribute to LLEC formation and maintenance, as well as determine how LLEC function contributes to memory responses in COH mice. I have found that COH LLEC are more polyfunctional compared to SPF LLEC, and my preliminary work has found that LLEC turnover is increased in COH mice. Future studies will determine what specific inflammatory cues lead to LLEC expansion, and if this process can be altered to improve T cell responses to infection and vaccination. Supported by grants from the NIH (R01 AI155468)

SIMON, a powerful AI software accelerating discovery of human immune memory responses to viruses

Abstract Influenza and SARS-CoV-2 are among the greatest viral threats to human health causing the 20th and 21st centuries’ most significant pandemics. These viruses have caused millions of deaths worldwide and continue to pose a significant risk to global health. To effectively fight against these viruses, it is essential to understand the complexity behind the generation of immune memory responses. The traditional analytical methods are often inadequate for capturing the complexity of the immune responses. To address this challenge, we have developed SIMON, a new AI software that can perform integrative multi-omics analysis to study human immune memory responses. With an easy-to-use graphical user interface, standardized pipelines, automated approach for machine learning testing over 180 algorithms, and other statistical analysis methods, SIMON helps to identify crucial patterns in biomedical data. We have demonstrated the accuracy, ease of use, and power of our software on various biomedical datasets, gaining valuable insights into the mechanisms underlying immunity to SARS-CoV-2 and influenza. This knowledge can be used to develop more effective vaccines and help researchers better understand the long-term impact of SARS-CoV-2 or influenza viruses on the immune system. By predicting the immune memory responses, SIMON has the potential to accelerate the development of vaccines that provide long-term protection against these pandemic viruses. Overall, SIMON is a powerful software platform for data mining that facilitates pattern recognition and knowledge extraction from high-dimensional biomedical data. It has the potential to greatly accelerate discovery in human immunology and biomedicine.

BBIBP-CorV vaccination accelerates anti-viral antibody responses in heterologous Omicron infection: A retrospective observation study in Shanghai.

To investigate how BBIBP-CorV vaccination affecting antibody responses upon heterologous Omicron infection. 440 Omicron-infected patients were recruited in this study. Antibodies targeting SARS-CoV-2 spike protein receptor binding domain (RBD) and nucleoprotein of both wild-type (WT) and Omicron were detected by ELISA. The clinical relevance was further analyzed. BBIBP-CorV vaccinated patients exhibited higher anti-RBD IgG levels targeting both WT and Omicron than non-vaccinated patients at different stages. By using a 3-day moving average analysis, we found that BBIBP-CorV vaccinated patients exhibited the increases in both anti-WT and Omicron RBD IgG from the onset and reached the plateau at Day 8 whereas those in non-vaccinated patients remained low during the disease. Significant increase in anti-WT RBD IgA was observed only in vaccinated patients. anti-Omicron RBD IgA levels remained low in both vaccinated and non-vaccinated patients. Clinically, severe COVID-19 only occurred in non-vaccinated group. anti-RBD IgG and IgA targeting both WT and Omicron were negatively correlated with virus load, hospitalization days and virus elimination in vaccinated patients. BBIBP-CorV vaccination effectively reduces the severity of Omicron infected patients. The existence of humoral memory responses established through BBIBP-CorV vaccination facilitates to induce rapid recall antibody responses when encountering SARS-CoV-2 variant infection.

Can regulatory T cells improve outcomes of sensitised patients after HLA-Ab incompatible renal transplantation: study protocol for the Phase IIa GAMECHANgER-1 trial

BackgroundKidney transplantation is the gold-standard treatment for patients with kidney failure. However, one-third of patients awaiting a kidney transplant are highly sensitized to human leukocyte antigens (HLA), resulting in an increased waiting time for a suitable kidney, more acute and chronic rejection, and a shorter graft survival compared to non-highly sensitised patients. Current standard immunosuppression protocols do not adequately suppress memory responses, and so alternative strategies are needed. Autologous polyclonally expanded regulatory T cells (Tregs) have been demonstrated to be safe in transplant settings and could be a potential alternative to modulate memory immune alloresponses.MethodsThe aim of this trial is to determine whether adoptive transfer of autologous Tregs into HLA sensitised patients can suppress memory T and B cell responses against specific HLA antigens. This is a two-part, multi-centre, prospective clinical trial, comprising an observational phase (Part 1) aiming to identify patients with unregulated cellular memory responses to HLA (Pure HLA Proteins) followed by an interventional phase (Part 2). The first 9 patients identified as being eligible in Part 1 will undergo baseline immune monitoring for 2 months to inform statistical analysis of the primary endpoint. Part 2 is an adaptive, open labelled trial based on Simon’s two-stage design, with 21 patients receiving Good Manufacturing Practice (GMP)-grade polyclonally expanded Tregs to a dose of 5–10 × 106 cells/kg body weight. The primary EP is suppression of in vitro memory responses for 2 months post-infusion. 12 patients will receive treatment in stage 1 of Part 2, and 9 patients will receive treatment in stage 2 of Part 2 if ≥ 50% patients pass the primary EP in stage 1.DiscussionThis is a prospective study aiming to identify patients with unregulated cellular memory responses to Pure HLA Proteins and determine baseline variation in these patterns of response. Part 2 will be an adaptive phase IIa clinical trial with 21 patients receiving a single infusion of GMP-grade polyclonally expanded Tregs in two stages. It remains to be demonstrated that modulating memory alloresponses clinically using Treg therapy is achievable.Trial registrationEudraCT Number: 2021–001,664-23.REC Number: 21/SC/0253.Trial registration number ISRCTN14582152.

Dual-Acting Small Molecules: Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer's Disease Mouse Model.

We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabinoid receptor 2 (hCB2R) ligands for the treatment of neurodegeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholinesterases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a β-arrestin 2 (βarr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood-brain barrier penetration. Compound 15d, containing a dimethyl carbamate motif, was further evaluated in vivo, showing prevention of Aβ25-35-induced learning impairments in a pharmacological mouse model of Alzheimer's disease for both short- and long-term memory responses. Additional combination studies proved a synergic effect of BChE inhibition and CB2R activation in vivo.

Human CD4 cytotoxic T lymphocytes mediate potent tumor control in humanized immune system mice

Efficacy of immune checkpoint inhibitors in cancers can be limited by CD8 T cell dysfunction or HLA-I down-regulation. Tumor control mechanisms independent of CD8/HLA-I axis would overcome these limitations. Here, we report potent CD4 T cell-mediated tumor regression and memory responses in humanized immune system (HIS) mice implanted with HT-29 colorectal tumors. The regressing tumors showed increased CD4 cytotoxic T lymphocyte (CTL) infiltration and enhanced tumor HLA-II expression compared to progressing tumors. The intratumoral CD4 T cell subset associated with tumor regression expressed multiple cytotoxic markers and exhibited clonal expansion. Notably, tumor control was abrogated by depletion of CD4 but not CD8 T cells. CD4 T cells derived from tumor-regressing mice exhibited HLA-II-dependent and tumor-specific killing ex vivo. Taken together, our study demonstrates a critical role of human CD4 CTLs in mediating tumor clearance independent of CD8 T cells and provides a platform to study human anti-tumor immunity in vivo.

Memory profiles distinguish cross-reactive and virus-specific T cell immunity to mpox

Mpox represents a persistent health concern with varying disease severity. Reinfections with mpox virus (MPXV) are rare, possibly indicating effective memory responses to MPXV or related poxviruses, notably vaccinia virus (VACV) from smallpox vaccination. We assessed cross-reactive and virus-specific CD4+ and CD8+ Tcells in healthy individuals and mpox convalescent donors. Cross-reactive Tcells were most frequently observed in healthy donors over 45 years. Notably, long-lived memory CD8+ Tcells targeting conserved VACV/MPXV epitopes were identified in older individuals more than four decades after VACV exposure and exhibited stem-like characteristics, defined by Tcell factor-1 (TCF-1) expression. In mpox convalescent donors, MPXV-reactive CD4+ and CD8+ Tcells were more prevalent than incontrols, demonstrating enhanced functionality and skewing toward effector phenotypes, which correlated with milder disease. Collectively, we report robust effector memory MPXV-specific Tcell responses in mild mpox and long-lived TCF-1+ VACV/MPXV-specific CD8+ Tcells decades after smallpox vaccination.

Shape memory mechanical metamaterials

Shape memory materials can maintain temporary shapes without external constraints and revert to their permanent shape upon exposure to an external stimulus, such as heat, light, or moisture. This behavior, often named the shape memory effect, has led to the use of shape memory materials in a variety of applications including deployable aerospace structures, biomedical devices, flexible electronics, and untethered soft robots. Most thermally triggered reconfigurable metamaterials using shape memory polymers require a laborious process of thermomechanical programming at high temperature, above their transition value, to maintain a temporary shape. In this paper, we utilize two 3D-printable polymeric materials that do not rely upon their shape memory effect to generate robust shape memory response in a set of mechanical metamaterials. The enabling characteristic is the mismatch of the temperature-dependent moduli of the constitutive materials leveraged in rationally interconnected reconfigurable units, and their hallmark is the freedom to forego the complex programming process of typical shape memory polymers. Their shape reconfiguration and rapid recovery are solely governed by mechanical loading and temperature change, leading to sequentially programmable multistability, hyperelasticity, giant thermal deformations, and shape memory capacity. Theoretical models, numerical simulations, and thermomechanical experiments are performed to demonstrate their functionality, stability transition mechanism, and potential applications.

Contributions of transient and sustained reward to memory formation.

Reward benefits to memory formation have been robustly linked to dopaminergic activity. Despite the established characterization of dopaminergic mechanisms as operating at multiple timescales, potentially supporting distinct functional outcomes, the temporal dynamics by which reward might modulate memory encoding are just beginning to be investigated. In the present study, we leveraged a mixed block/event experimental design to disentangle transient and sustained reward influences on task engagement and subsequent recognition memory in an adapted monetary-incentive-encoding (MIE) paradigm. Across three behavioral experiments, transient and sustained reward modulation of item and context memory was probed, at both 24-h and ~ 15-min retention intervals, to investigate the importance of overnight consolidation. In general, we observed that transient reward was associated with enhanced item memory encoding, while sustained reward modulated response speed but did not appear to benefit subsequent recognition accuracy. Notably, reward effects on item memory performance and response speed were somewhat inconsistent across the three experiments, with suggestions that RT speeding might also be related to time on task, and we did not observe reward modulation of context memory performance or amplification of reward benefits to memory by overnight consolidation. Taken together, the observed pattern of behavior is consistent with potentially distinct roles for transient and sustained reward in memory encoding and cognitive performance and suggests that further investigation of the temporal dynamics of dopaminergic contributions to memory formation will advance the understanding of motivated memory.

Double poro-magneto-thermoelastic model with microtemperatures and initial stress under memory-dependent heat transfer

The memory response of an initially stressed half-space comprising a double poro-magneto-thermoelastic material with voids and microtemperatures (DPMTMWVM) under the dual-phase-lag heat conduction law is investigated in this article. With the aid of normal mode technique, the non-dimensional equations of motion are solved to derive the theoretical expressions of the displacements, temperature, microtemperatures, void volume fractions, stresses, and heat flux moments. The impacts of magnetic field, kernel functions, and initial stress on the aforementioned distributions are demonstrated through several graphs. Moreover, the memory-dependent Lord-Shulman and dual-phase-lag thermoelasticity theories are compared graphically to exhibit the variations in the field variables. To the best of the authors’ knowledge, the memory response of a double poro-magneto-thermoelastic half-space with voids and microtemperatures is not analyzed so far. Therefore, DPMTMWVM under memory-dependent dual-phase-lag theory is considered in this study.