T-cell Memory Formation Research Articles

Cross-species single-cell RNA sequencing reveals divergent phenotypes and activation states of adaptive immunity in human carotid and experimental murine atherosclerosis.

The distinct functions of immune cells in atherosclerosis have been mostly defined by preclinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression is only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches. Single cell RNA-sequencing (scRNA-seq) was performed to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire demonstrated an unexpectedly high heterogeneity and was dominated by cells of the T-cell lineage, a finding confirmed by immunohistochemistry. Bioinformatical integration with 7 mouse scRNA-seq data sets from adventitial and atherosclerotic vascular tissue revealed a total of 51 identities of cell types and differentiation states, of which some were only poorly conserved between species and exclusively found in humans. Locations, frequencies, and transcriptional programs of immune cells in mouse models did not resemble the immune cell landscape in human carotid atherosclerosis. In contrast to standard mouse models of atherosclerosis, human plaque leukocytes were dominated by several T-cell phenotypes with transcriptional hallmarks of T-cell activation and memory formation, T-cell receptor-, and pro-inflammatory signaling. Only mice at the age of 22 months partially resembled the activated T-cell phenotype. In a validation cohort of 43 patients undergoing carotid endarterectomy, the abundance of activated immune cell subsets in the plaque defined by multi-color flow cytometry associated with the extend of clinical atherosclerosis. Integrative scRNA-seq reveals a substantial difference in the immune cell composition of murine and human carotid atherosclerosis - a finding that questions the translational value of standard mouse models for adaptive immune cell studies. Clinical associations suggest a specific role for T-cell driven (auto-) immunity in human plaque formation and -instability.

ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection

The maintenance of antigen-specific CD8+ Tcells underlies the efficacy of vaccines and immunotherapies. Pathways contributing to CD8+ Tcell loss are not completely understood. Uncovering the pathways underlying the limited persistence of CD8+ Tcells would be of significant benefit for developing novel strategies of promoting Tcell persistence. Here, we demonstrate that murine CD8+ Tcells experience endoplasmic reticulum (ER) stress following activation and that the ER-associated degradation (ERAD) adapter Sel1L is induced in activated CD8+ Tcells. Sel1L loss limits CD8+ Tcell function and memory formation following acute viral infection. Mechanistically, Sel1L is required for optimal bioenergetics and c-Myc expression. Finally, we demonstrate that human CD8+ Tcells experience ER stress upon activation and that ER stress is negatively associated with improved Tcell functionality in Tcell-redirecting therapies. Together, these results demonstrate that ER stress and ERAD are important regulators of Tcell function and persistence.

Rapamycin improves the long-term T-cell memory and protective efficacy of tuberculosis subunit vaccine

The formation of long-lived T-cell memory is a critical goal of vaccines against intracellular pathogens like Mycobacterium tuberculosis (M. tuberculosis). In this study, to access the adjuvant effect of rapamycin on tuberculosis subunit vaccine, we treated mice with rapamycin during the course of vaccination and then monitored the vaccine-specific long-term memory T cell recall responses and protective ability against mycobacterial organisms. Compared with the mice that received vaccine alone, rapamycin treatment enhanced the vaccine induced long-term IFN-γ and IL-2 recall responses, promoted the development of TCM (central memory) like cells and improved the long-term proliferative ability of lymphocytes. Long-duration (total 53 days) of low-dose rapamycin (75 μg/kg/day) treatment generated stronger vaccine-specific memory T cell responses than short-duration treatment (total 25 days). Moreover, rapamycin improved the vaccine's long-term protective efficacy, which resulted in a better reduction of 0.89-log10 CFU of mycobacterial organisms in the lungs compared with control without rapamycin treatment. These findings suggest that rapamycin may be considered in designing TB subunit vaccine regimens or as potential adjuvant to enhance vaccine-induced T cell memory response and to prolong the longevity of vaccine's protective efficacy.

Abstract 1354: Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1

Abstract Distinct effects on T-cell differentiation arise from immune checkpoint inhibition targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1). However, the effect of these immunotherapies on the immunological memory response remains unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T-cell formation in mice revealed that anti-CTLA-4 generates a more effective memory antitumor response than anti-PD-1. Memory T-cells arising after anti-CTLA-4 treatment exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more TCF-1+ T-cells during priming, while anti-PD-1 leads to more TOX+ T-cells. Experiments using conditional TCF-1- or TOX-knockout mice highlight TCF-1 is essential for memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system. Citation Format: Stephen Mok, Huey Liu, Nana-Ama A.S. Anang, James J. Mancuso, Didem Ağaç Çobanoğlu, James P. Allison. Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1 [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 1354.

Double-layered N-S1 protein nanoparticle immunization elicits robust cellular immune and broad antibody responses against SARS-CoV-2

BackgroundThe COVID-19 pandemic is a persistent global threat to public health. As for the emerging variants of SARS-CoV-2, it is necessary to develop vaccines that can induce broader immune responses, particularly vaccines with weak cellular immunity.MethodsIn this study, we generated a double-layered N-S1 protein nanoparticle (N-S1 PNp) that was formed by desolvating N protein into a protein nanoparticle as the core and crosslinking S1 protein onto the core surface against SARS-CoV-2.ResultsVaccination with N-S1 PNp elicited robust humoral and vigorous cellular immune responses specific to SARS-CoV-2 in mice. Compared to soluble protein groups, the N-S1 PNp induced a higher level of humoral response, as evidenced by the ability of S1-specific antibodies to block hACE2 receptor binding and neutralize pseudovirus. Critically, N-S1 PNp induced Th1-biased, long-lasting, and cross-neutralizing antibodies, which neutralized the variants of SARS-CoV-2 with minimal loss of activity. N-S1 PNp induced strong responses of CD4+ and CD8+ T cells, mDCs, Tfh cells, and GCs B cells in spleens.ConclusionsThese results demonstrate that N-S1 PNp vaccination is a practical approach for promoting protection, which has the potential to counteract the waning immune responses against SARS-CoV-2 variants and confer broad efficacy against future new variants. This study provides a new idea for the design of next-generation SARS-CoV-2 vaccines based on the B and T cells response coordination.Graphical Steps involved in the preparation of double-layered N-S1 protein nanoparticle vaccines and experimental design performed in combating virus infection. After intramuscular immunization of mice, the double-layered N-S1 protein nanovaccine could effectively promote the maturation of antigen-presenting and mature dendritic cells, robust broad-spectrum neutralizing antibody production, cytokines secretion, robust mDC, Tfh cell, and GCs B cell responses induction, T-cell memory formation and durable antibody responses, and unique global transcriptome characteristics, thus achieving a robust cellular immunity and broad antibody responses against SARS-CoV-2 based on the B and T cells response coordination

Abstract A054: Anti-CTLA-4 generates memory T-cell with greater expansion and functionality than anti-PD-1

Abstract Blocking either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed cell death-1 (PD-1) pathway results in distinct T-cell differentiation. We investigated the effects of anti-CTLA-4 and anti-PD-1 on memory T-cell formation in mice. Anti-CTLA-4 generates a more potent memory response than anti-PD-1. Memory T-cells generated by anti-CTLA-4 expand at a greater frequency, have greater cytokine production, and exhibit higher antitumor activity than those generated by anti-PD-1. These memory cells also more frequently differentiate into KLRG1+ effector CD8 T-cells during re-challenge. Additionally, anti-CTLA-4 generates more TCF-1+ memory-like T-cells, while anti-PD-1 results in more TOX+ terminally differentiated T-cells. Together, we provide insights into the long-term effects of these immunotherapies on the immune system. Citation Format: Stephen Mok, Huey Liu, Nana-Ama A.S. Anang, James J Mancuso, Didem Ağaç Çobanoğlu, James P Allison. Anti-CTLA-4 generates memory T-cell with greater expansion and functionality than anti-PD-1 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A054.

Mitochondrial Isocitrate Dehydrogenase Inhibition Enhances CAR T-Cell Function By Restraining Antioxidant Metabolism and Histone Acetylation

Introduction: The efficacy of chimeric antigen receptor (CAR) T-cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Mitochondria are vital for the regulation of memory T-cell formation or exhaustion. A mitochondria-related compound screening was performed and we found that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances long-lived memory CAR T-cell formation, and improves tumor clearance in vivo. IDH2 as the key component of the tricarboxylic acid (TCA) cycle, we hypothesized that IDH2 inhibition might promote CAR T-cell persistence by reprogramming the metabolism. The study aims to systematically evaluate the role and the mechanism of IDH2 inhibition on CAR T cells, and explore the application of enasidenib in CAR T-cell therapy. Methods and Results: To identify mitochondrial components that affect the long-term efficacy of CAR T-cells, we performed an in vitro screening using a mitochondria-related compound library based on the enrichment of the CD62L + CAR T-cell subset, which mainly contains T memory stem cells (T SCM) and central memory T cells (T CM). Among several candidate compounds that promoted memory CAR T-cell formation, enasidenib (ENA), an inhibitor of both wild-type and mutant IDH2 enzymes, was the most effective one. The proportion of CD62L has increased by over 20%. To determine the effect of ENA on exhaustion induced by tonic CAR signaling and tumor antigen stimulation, we measured the expression of inhibitory receptors PD-1, TIM-3, and LAG-3 and the level of apoptosis in freshly expanded CAR T cells and B-ALL encountered CAR T cells. CAR T cells treated with ENA exhibited reduced surface levels of those inhibitory receptors. We measured the production of granzyme B and IFNγ, and tumor rechallenge assay in CAR T cells after ENA treatment to assess the effector function, ENA treated CAR T cells exerted enhanced and sustained cytotoxicity in a tumor rechallenge assay at an extreme E:T ratio of 1:10. These results were observed not only in CD19-41BBζ CAR T cells, but also in CD19-28ζ and GD2-28ζ CAR T cells. CAR T cells expanded in the presence of ENA significantly prolonged survival of recipients after Nalm-6 infusion (p < 0.0001), extended in vivo ENA treatment further enhanced CAR T-cell expansion and tumor suppression. The median survival was extended from 45 to 67.5 days. Consistent with the effect of ENA treatment, IDH2 knockdown increased the proportions of the T scm/T n and T cm subsets, and alleviated CAR T-cell exhaustion. IDH2-knockdown CAR T cells had sustained cytotoxicity and higher CD62L expression after rounds of killing B-ALL cells in vitro. To systematically explore the effects of IDH2 inhibition on the metabolism of CAR T cells, relative metabolite amounts was measured using mass spectrometry (MS). IDH2-inhibited CAR T cells exhibited a substantial reduction of metabolites in the TCA cycle, including succinate, fumarate, and malate, and in the glycolysis pathway, including lactate, phosphoenolpyruvate. Mechanistically, IDH2 inhibition reprogram central carbon metabolism of CAR T cells by redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway. In addition, IDH2 limits cytosolic acetyl-CoA level to prevent histone acetylation that promotes memory cell formation. Significance: Our study indicates that metabolic intervention in CAR T cells with the FDA-approved IDH2 inhibitor enasidenib can advance current treatment, with better tumor eradication and CAR T-cell persistence.

EXTH-09. GM-CSF AND IL-7 FUSION CYTOKINE ENGINEERED TUMOR VACCINE GENERATES LONG-TERMTH-17 MEMORY CELLS AND INCREASES OVERALL SURVIVAL IN AGED SYNGENEIC MOUSE MODELS OF GLIOBLASTOMA

Abstract 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 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 anti-tumor immunity specifically in aged mice. Global cytokine analysis showed increased pro-inflammatory cytokines including IL-1b 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 anti-tumor immunity.

Metabolic programs of T cell tissue residency empower tumour immunity.

Tissue resident memoryCD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memoryCD8+ T cell populations. We found that memory CD8+T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memoryT cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memoryCD8+ T cell formation in the context of acute infections and enhance antitumour immunity.

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.

Pim2 negatively regulates T-cell immune responses through modulating autophagy

Abstract Pim kinases affect cell survival, cell proliferation, transcriptional activation, and protein translation by phosphorylating various target substrates. We previously showed that Pim2 plays a distinct role from Pim1 and Pim3, and negatively regulates T-cell allogeneic response and anti-tumor immunity. Pim2 was reported to promote the induction of autophagy in cancer cells, a cellular process that critically impacts T-cell effector function, survival and memory formation. We hypothesize that Pim2 constrains T-cell immune responses through modulating autophagy. Using western blot and electron microscopy, we evaluated the effect of Pim2 on autophagic flux in resting and activated T cells. Pim2 deficiency in T cells attenuated LC3 lipidation, P62 degradation as well as autophagosome formation, suggesting that Pim2 facilitates autophagy in T cells. Mechanistically, Pim2 directly bound with P62 and loss of Pim2 led to accumulation of P62 which further blocked autophagic flux in T cells. Furthermore, augmentation of autophagy via overexpressing Atg5 or metformin treatment reduced effector cytokine production in Pim2-deficient T cells in vitroand reversed the heightened ability of Pim2-deficient T cells for inducing graft-versus-host disease and for controlling breast cancer growth in vivo. Taken together, Pim2 is a key promotor of autophagy in T cells and targeting Pim2 to suppress autophagy may represent a promising strategy to improve T-cell effector function in cancer immunotherapy. The work was supported by NIH grants: R01 CA258440 and R21 CA263140.

Agonistic anti-CD27 antibody ameliorates EAE by suppressing IL-17 production.

CD27/CD70 costimulation enhances T-cell survival, memory formation and Th1-cell differentiation and effector function. In addition to promoting Th1 responses, CD27 signaling has been shown to exert a negative regulatory role on IL-17 production, resulting in increased sensitivity of CD27 KO mice to EAE. By inducing EAE in full CD27 KO mice, and in a novel, T-cell specific CD27 KO mouse strain (CD4-Cre x CD27flox/flox ), we demonstrate herein that CD27 engagement by its natural ligand (CD70) suppresses IL-17 production in a cell autonomous fashion. We further show that CD27 engagement by an agonistic antibody given after EAE induction or at symptom onset similarly suppresses IL-17 production by activated CD4+ T cells infiltrating the inflamed CNS while IFN-γ production was unaffected, leading to an amelioration of inflammatory-related symptoms. These findings propose CD27 costimulation as a potential candidate for therapeutic manipulation to treat autoimmune and autoinflammatory diseases characterized by excessive IL-17 production.

T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy.

Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.

STAT3 Role in T-Cell Memory Formation.

Along with the clinical success of immuno-oncology drugs and cellular therapies, T-cell biology has attracted considerable attention in the immunology community. Long-term immunity, traditionally analyzed in the context of infection, is increasingly studied in cancer. Many signaling pathways, transcription factors, and metabolic regulators have been shown to participate in the formation of memory T cells. There is increasing evidence that the signal transducer and activator of transcription-3 (STAT3) signaling pathway is crucial for the formation of long-term T-cell immunity capable of efficient recall responses. In this review, we summarize what is currently known about STAT3 role in the context of memory T-cell formation and antitumor immunity.

Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation.

CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. SIGNIFICANCE: CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade.This article is highlighted in the In This Issue feature, p. 2355.

CD4+ Memory T-Cell Formation during Type 1 Immune Responses.

Naive CD4+ T cells become memory cells after proliferating in response to their cognate major histocompatibility complex class II (MHCII)-bound peptide and passing through an effector cell stage. The process by which CD4+ memory T cells emerge from the effector cell pool, however, is less well understood than in the case of CD8+ T cells. During certain acute infections, naive CD4+ T cells proliferate and differentiate into various forms of type 1 (Th1) and follicular helper (Tfh) effector cells. We review the evidence that about 10% of the cells in each of these subsets survive to become memory cells that resemble their effector cell precursors. The roles that asymmetric cell division, the TCF-1 transcription factor, metabolic activity, reactive oxygen species, and the IL-7 receptor play in the effector to memory cell transition are discussed. We propose a speculative model in which the metabolic activity needed for rapid clonal expansion also generates toxic products that induce apoptosis in most effector cells. Memory cells then arise from the effector cells in each subset that are at the low end of the metabolic activity spectrum.

A Phase 1 Study of KHK4083: A Single‐Blind, Randomized, Placebo‐Controlled Single‐Ascending‐Dose Study in Healthy Adults and an Open‐Label Multiple‐Dose Study in Patients With Ulcerative Colitis

OX40 plays an essential role in maintaining late T‐cell proliferation and survival by suppressing apoptosis and by inducing T‐cell memory formation. Here, we report the results of the phase 1 study of KHK4083, a fully human antimonoclonal antibody specific for OX40. In this study, we aimed to assess the safety and tolerability of a single intravenous or subcutaneous administration of KHK4083 compared with placebo in healthy Japanese and Caucasian subjects and determined the pharmacokinetics (PK) and immunogenicity. Also, we assessed the preliminary efficacy and pharmacodynamics of multiple intravenous doses in Japanese patients with moderate to severe ulcerative colitis (UC). Drug‐related treatment emergent adverse events occurred in 21 healthy subjects (58.3%) and 5 patients with UC (62.5%) after administration of KHK4083. There were no serious adverse events. The PK profile of a single intravenous dose of 10 mg/kg KHK4083 was similar in healthy Japanese and Caucasian subjects. Of 8 UC patients, a clinical response was observed in 3 patients (37.5%) and clinical remission in 2 patients (25.0%) in week 6. Our study demonstrated the safety and tolerability of single and multiple administrations of KHK4083 in healthy Japanese and Caucasian subjects and Japanese patients with moderate to severe UC. It also indicated favorable pharmacological properties of the drug.

Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T-cell memory formation after mild COVID-19 infection.

COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. T cells play a key role in the adaptive antiviral immune response by killing infected cells and facilitating the selection of virus-specific antibodies. However, neither the dynamics and cross-reactivity of the SARS-CoV-2-specific T-cell response nor the diversity of resulting immune memory is well understood. In this study, we use longitudinal high-throughput T-cell receptor (TCR) sequencing to track changes in the T-cell repertoire following two mild cases of COVID-19. In both donors, we identified CD4+ and CD8+ T-cell clones with transient clonal expansion after infection. We describe characteristic motifs in TCR sequences of COVID-19-reactive clones and show preferential occurrence of these motifs in publicly available large dataset of repertoires from COVID-19 patients. We show that in both donors, the majority of infection-reactive clonotypes acquire memory phenotypes. Certain T-cell clones were detected in the memory fraction at the pre-infection time point, suggesting participation of pre-existing cross-reactive memory T cells in the immune response to SARS-CoV-2.

Beyond energy storage: roles of glycogen metabolism in health and disease.

Beyond storing and supplying energy in the liver and muscles, glycogen also plays critical roles in cell differentiation, signaling, redox regulation, and stemness under various physiological and pathophysiological conditions. Such versatile functions have been revealed by various forms of glycogen storage diseases. Here, we outline the source of carbon flux in glycogen metabolism and discuss how glycogen metabolism guides CD8+ T-cell memory formation and maintenance. Likewise, we review how this affects macrophage polarization and inflammatory responses. Furthermore, we dissect how glycogen metabolism supports tumor development by promoting tumor-repopulating cell growth in hypoxic tumor microenvironments. This review highlights the essential role of the gluconeogenesis-glycogenesis-glycogenolysis-PPP metabolic chain in redox homeostasis, thus providing insights into potential therapeutic strategies against major chronic diseases including cancer.

Engineering CD4+ T Cells to Enhance Cancer Immunity.

This review presents key advances in combining T cell receptor (TCR) gene transfer to redirect T-cell specificity with gene engineering in order to enhance cancer-protective immune function. We discuss how emerging insights might be applied to CD4+ T cells. Although much attention has been paid to the role of CD8+ cytotoxic T cells in tumour protection, we provide convincing evidence that CD4+ helper T cells play a critical role in cancer immune responses in animal models and also in patients. We demonstrate that genetic engineering technologies provide exciting opportunities to extend the specificity range of CD4+ T cells from MHC class-II-presented epitopes to include peptides presented by MHC class I molecules. Functional enhancement of tumour immunity can improve the sensitivity of T cells to cancer antigens, promote survival in a hostile tumour microenvironment, boost cancer-protective effector mechanisms and enable the formation of T-cell memory. Engineered cancer-specific CD4+ T cells may contribute to protective immunity by a direct pathway involving cancer cell killing, and by an indirect pathway that boosts the function, persistence and memory formation of CD8+ T cells.