Search

CD8+ T cells are end effectors of cancer immunity. Most forms of effective cancer immunotherapy involve CD8+ T cell effector function. Here, we review the current understanding of T cell function in cancer, focusing on key CD8+ T cell subtypes and states. We discuss factors that influence CD8+ T cell differentiation and function in cancer through a framework that incorporates the classic three-signal model and a fourth signal—metabolism—and also consider the impact of the tumor microenvironment from a T cell perspective. We argue for the notion of immunotherapies as "pro-drugs" that act to augment or modulate T cells, which ultimately serve as the drug in vivo , and for the importance of overall immune health in cancer treatment and prevention. The progress in understanding T cell function in cancer has and will continue to improve harnessing of the immune system across broader tumor types to benefit more patients. CD8+ T cells are "end effectors" of cancer immunity. Wherry, Kaech, and colleagues review the current understanding of CD8+ T cell differentiation and function in cancer, discussing recent advances within a four-signal framework that incorporates T cell metabolism and the impact of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

T cells patrol our bodies preventing pathogenic infections and malignant cell outgrowth. However, T cells must be properly controlled because aberrant or persistent T cell responses can damage tissues and contribute to autoimmune diseases and other chronic inflammatory diseases including metabolic syndrome. One regulatory mechanism utilized in immune cells is immunometabolic regulation, which ensures immune cells properly respond to systemic and peripheral metabolic cues. Recent work has suggested that deregulated metabolism in tumor cells creates a microenvironmental barrier for mounting effective anti-tumor immune responses. Here, we discuss how tumor cells evade immunosurveillance by modulating metabolic checkpoints in immune cells and discuss how memory T cells could provide effective anti-tumor responses by sustaining metabolic fitness and longevity. [ABSTRACT FROM AUTHOR]

In the tumor microenvironment, immune cells and tumor cells interact in a process called cancer immunoediting, giving rise to changes in gene expression, metabolism, mutational burden, and cellularity in the tumor. This SnapShot compares endogenous versus therapy-induced cancer immunoediting and outlines the molecular and cellular characteristics of interactions that result in complete tumor regression versus tumor escape and progression. To view this SnapShot, open or download the PDF. [ABSTRACT FROM AUTHOR]

Immunity to many intracellular pathogens requires the proliferation, differentiation, and function of CD8+ cytotoxic T lymphocytes ( CTLs). While the majority of effector CTLs die upon clearance of the pathogen, a small proportion of them survive to become long-lived memory CTLs. Memory CTLs can provide protective immunity against re-exposure to the same pathogen and are the principle motivation behind T-cell- based vaccine design. While a large body of cellular immunologic research has proven invaluable to define effector and memory CTLs by their different phenotypes and functions, an emerging focus in the field has been to understand how environmental cues regulate CTL differentiation on a genomic level. Genome-wide studies to profile transcriptional and epigenetic changes during infection have revealed that dynamic changes in DNA methylation patterns and histone modifications accompany transcriptional signatures that define and regulate CTL differentiation states. In this review, we emphasize the importance of epigenetic regulation of CD8+ T-cell differentiation and the likely role that transcription factors play in this process. [ABSTRACT FROM AUTHOR]

During an infection, T cells can differentiate into multiple types of effector and memory T cells, which help to mediate pathogen clearance and provide long-term protective immunity. These cells can vary in their phenotype, function and location, and in their long-term fate in terms of their ability to populate the memory T cell pool. Over the past decade, the signalling pathways and transcriptional programmes that regulate the formation of heterogeneous populations of effector and memory CD8+ T cells have started to be characterized, and this Review discusses the major advances in these areas. [ABSTRACT FROM AUTHOR]

Immunological memory is a cardinal feature of adaptive immunity. We are now beginning to elucidate the mechanisms that govern the formation of memory T cells and their ability to acquire longevity, survive the effector-to-memory transition, and mature into multipotent, functional memory T cells that self-renew. Here, we discuss the recent findings in this area and highlight extrinsic and intrinsic factors that regulate the cellular fate of activated CD8+ T cells. [ABSTRACT FROM AUTHOR]

Summary: In response to acute infections or vaccines, naive antigen-specific CD8+ T cells proliferate and differentiate into effector cytotoxic lymphocytes that acquire the ability to kill infected cells. While the majority of differentiated effector cells die after pathogen clearance, a small number evade terminal differentiation, downregulate active effector functions, and survive as long-lived, self-renewing memory T cells. Our understanding of how effector CD8+ T cells adopt these different cell fates has grown greatly in recent years. In this review, we discuss the transcriptional regulators that are known to support general effector differentiation, terminal effector differentiation, and memory cell formation. We propose that the diversity of activated CD8+ T-cell differentiation states is achieved via gradients of activity or expression of transcriptional regulators that are regulated by the level of inflammation and antigenic signaling the T cells experience during infection. [ABSTRACT FROM AUTHOR]

T cell dysfunction in cancer comes in many forms, with two new varieties reported in this issue. Daley et al. find that T cells expressing γδ T cell receptors (TCR) promote pancreatic tumor growth by inhibiting activation of T cells with conventional TCRs. Singer et al. characterize dysfunctional tumor infiltrating lymphocytes to reveal a role for zinc homeostasis in anti-tumor immunity. [ABSTRACT FROM AUTHOR]

CD8+ T cells are key effector cells of the adaptive immune system, however their activity must be tightly regulated to allow pathogen clearance whilst preventing immunopathology and autoimmunity. In this review, we summarise the diversity of responses that CD8+ T cells make to antigenic stimulation with a focus on how CD8+ T cell responses are regulated to achieve different immune outcomes. In particular, we discuss phenotypic diversity during tolerance induction as well as signals that drive effector and memory cell differentiation in response to infection. [Copyright &y& Elsevier]

Heterogeneity is a hallmark of the adaptive immune system. This is most evident in the enormous diversity of B and T cell antigen receptors. There is also heterogeneity within antiviral T cell populations, and subsets of effector and memory T cells now permeate our thinking about specialization of T cell responses to pathogens. It has been less clear, however, how heterogeneity in developing virus-specific effector and memory T cells is related to cell-fate decisions in the immune response, such as the generation long-lived memory T cells. Here we discuss recent findings that might help redefine how heterogeneity in antiviral T cell populations gives rise to T cell subsets with short- and long-lived cell fates. [Copyright &y& Elsevier]

Unlike naive CD8+ T cells, antigen-experienced memory CD8+ T cells persist over time due to their unique ability to homeostatically proliferate. It was hypothesized that memory cells might differentially regulate the expression of genes that control the cell cycle to facilitate homeostatic proliferation. To test this, the expression levels of 96 different cell cycle regulatory genes were compared between transgenic naive and memory CD8+ T cells that specifically recognize the GP33-41 epitope of lymphocytic choriomeningitis virus (LCMV). It was discovered that relative to naive cells, memory cells overexpress several important genes that control the transition between G1 and S phase. Some of these genes include those encoding cyclins D3, D2, B1, C, and H, cyclin-dependent kinases (cdk's) 4 and 6, the cdk inhibitors p16, p15, and p18, and other genes involved in protein degradation and DNA replication. Importantly, these differences were observed both in total populations of LCMV-specific naive and memory CD8+ cells and in LCMV-specific CD8+ T-cell populations that were in the G1 phase of the cell cycle only. In addition, the expression differences between naive and memory cells were exaggerated following antigenic stimulation. The fact that memory cells are precharged with several of the major factors that are necessary for the G1- to-S-phase transition suggests they may require a lower threshold of stimulation to enter the cell cycle. [ABSTRACT FROM AUTHOR]

Recent studies suggest that memory T-cell differentiation continues for weeks or months following antigen clearance, although commitment to the memory lineage occurs during the effector stage of development. Several variables associated with priming, such as the duration of antigenic stimulation, degree of co-stimulation, cytokine environment, and CD4+ T-cell help, may program epigenetic qualitative differences into the ensuing effector and memory populations. Defining what memory qualities best protect the organism from re-infection, as well as how commitment to the memory lineage is specified following T-cell activation remains an important goal. [Copyright &y& Elsevier]

A major unanswered question is what distinguishes the majority of activated CD8 T cells that die after an acute viral infection from the small fraction (5-10%) that survive to become long-lived memory cells. In this study we show that increased expression of the interleukin 7 receptor a-chain (IL-7Ra) identifies the effector CD8 T cells that will differentiate into memory cells. IL-7Rhi effector cells contained increased amounts of antiapoptotic molecules, and adoptive transfer of IL-7Rhi and IL-7Rlo effector cells showed that IL-7Rhi cells preferentially gave rise to memory cells that could persist and confer protective immunity. Thus, selective expression of IL-7R identifies memory cell precursors, and this marker may be useful in predicting the number of memory T cells generated after infection or immunization. [ABSTRACT FROM AUTHOR]

How and when memory T cells form during an immune response are long-standing questions. To better understand memory CD8 T cell development, a time course of gene expression and functional changes in antigen-specific T cells during viral infection was evaluated. The expression of many genes continued to change after viral clearance in accordance with changes in CD8 T cell functional properties. Even though memory cell precursors were present at the peak of the immune response, these cells did not display hallmark functional traits of memory T cells. However, these cells gradually acquired the memory cell qualities of self-renewal and rapid recall to antigen suggesting the model that antigen-specific CD8 T cells progressively differentiate into memory cells following viral infection. [Copyright &y& Elsevier]

Recent work shows that after stimulation with antigen, CD4+ and CD8+ T cells embark on a programme of proliferation that is closely linked with the acquisition of effector functions and leads ultimately to memory-cell formation. Here, we discuss the signals required for commitment to this programme of development and the factors that might influence its progression. Models of the pathways of effector and memory T-cell differentiation are discussed, and we highlight the implications of this new understanding for the optimization of vaccine strategies. [ABSTRACT FROM AUTHOR]

The rules that govern memory T cell differentiation are not well understood. This study shows that after antigenic stimulation naïve CD8+ T cells become committed to dividing at least seven times and differentiating into effector and memory cells. Once the parental naïve CD8+ T cell had been activated, this developmental process could not be interrupted and the daughter cells continued to divide and differentiate in the absence of further antigenic stimulation. These data indicate that initial antigen encounter triggers an instructive developmental program that does not require further antigenic stimulation and does not cease until memory CD8+ T cell formation. [ABSTRACT FROM AUTHOR]

Discusses the establishment and maintenance of epithelial cell polarity crucial for polarized cell functions. Genetic aspects of protein homolog; Protein interactions and enzymatic mechanisms of receptors; Requirements for basolateral membrane localization.

Reports on the occurrence of intercellular signaling between cells and tissues within multicellular organisms with a precisely defined geometry. How growth factors originate; What tight junctions forms around the lateral circumferences of vertebrate epithelial cells; Role played by cell signaling in polarized epithelial cells.

The article discusses a similar temporal and spatial division exists within the pool of memory T cells. Topics include subdivision of human memory T cells from the peripheral blood into multiple cell subsets based of the expression of different homing and chemokine receptors, responses of memory T cells, and the diversity of memory T cells.

Pathogen-induced inflammation modulates CD8 T cell effector and memory differentiation. In this issue of Immunity, Plumlee et al. (2013) demonstrate that clonally distinct CD8 T cells have the ability to generate numerous types of effector cell fates based on extrinsic pathogen-induced environmental cues. [ABSTRACT FROM AUTHOR]

report that the amount of antigenic stimulation initially sensed by naive CD8+ T cells can establish differentiation set points that are stably maintained in clonal progeny to promote functional diversity. [ABSTRACT FROM AUTHOR]

The article discusses a study which shows that memory CD8+ T cells can provide exceptionally long-term immunity against re-infection, which is in part because of their enhanced longevity and maintenance of a high proliferative capacity. During a viral infection, the activated CD8+ T cells undergo a vigorous wave of proliferation and differentiate into cytotoxic killer T cells that eliminate infected cells.

Memory T and B lymphocytes of the immune system provide long-term protection in response to bacterial or viral infections or immunization. Immunological protection depends on both the quality and quantity of memory T and B cells and of the long-lived plasma cells that secrete antibody. The long-term defense provided by memory CD8 T cells depends primarily on their ability to increase their numbers rapidly and exert potent effector responses. It also depends on their ability to persist for long periods through homeostatic proliferation and self-renewal ability. Although memory CD8 T cells are generated in the absence of CD4 T cells but still they display poorer recall responses than memory CD8 T cells generated with CD4 help.

Background: Stimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma. Methods: We employed a Simon's two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects. Results: Thirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses. Conclusions: Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options. Trial registration: ClinicalTrials.gov Identifier: NCT03502330. [ABSTRACT FROM AUTHOR]

Regulatory T cells are crucial for preventing autoimmunity, but how their function is restrained to allow optimal effector T cells responses in appropriate contexts is unclear. In a recent paper in the Journal of Experimental Medicine, Campbell and colleagues demonstrate that virus-induced type I interferon acts directly on Treg cells to allow for functional antiviral T cell responses. [ABSTRACT FROM AUTHOR]

Chronic viral infections represent a major burden to human health, and modulation of the immune system is emerging as a novel approach to fighting such infections. demonstrate that treatment with the cytokine IL-7 may reinvigorate the immune response to persistent infection by targeting immunosuppressive Socs3 proteins. [ABSTRACT FROM AUTHOR]

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell–mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex–antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially throughCI, provides proof of conceptof ETCrewiringtoachieve antitumor responses withoutsideeffects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion. [ABSTRACT FROM AUTHOR]

Recirculation of naive T cells between secondary lymphoid organs to receive survival cues and scan for signs of infection or other pathologic conditions is important for immune homeostasis and effective immune responses. Although the mechanisms that specifically guide the entry of naive T cells into secondary lymphoid organs are well studied, the mechanisms that keep them from fluxing into inappropriate or undesirable compartments, such as healthy tissues or bone marrow, are less well understood. In this study, we report an unexpected finding that under steady state, bone marrow homing of naive T cells is actively suppressed by mTORC2 signaling. We found that in mice, T cell--specific deletion of an essential mTORC2 component Sin1 results in increased accumulation of naive T cells in the bone marrow. Mechanistically, we show that loss of mTORC2 signaling in naive T cells results in enhanced FOXO1 activity, which leads to increased CXCR4 expression and chemotactic response to CXCL12, a key chemokine that promotes bone marrow homing and retention of T cells. Together, the results of our study reveal a novel role of mTORC2 in T cell homeostasis via active suppression of naive T cell bone marrow homing by the mTORC2--FOXO1--CXCR4 axis. [ABSTRACT FROM AUTHOR]

The establishment of an immunosuppressive tumor microenvironment is a hallmark feature driving cancer cell evasion of immunosurveillance. In a murine melanoma model, we recently demonstrated that decreased intratumoral CD4+T-cell expression of CD40L and interferon ? (IFN?) is critical to maintain this immunosuppressive microenvironment. Altered effector functions of tumor-associated CD4+T cells is essential for B-RafV600Einhibitor-mediated restoration of antitumor immunity. [ABSTRACT FROM PUBLISHER]

Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed. On September 5–8, 2022, experts in the field of immunometabolism met for the Keystone symposium "Immunometabolism at the Crossroads of Obesity and Cancer" to present recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer. Speakers highlighted new insights on the metabolic links between tumor cells and immune cells, with a focus on leveraging unique metabolic vulnerabilities of different cell types in the tumor microenvironment as therapeutic targets and demonstrated the effects of diet, the microbiome, and obesity on immune system function and cancer pathogenesis and therapy. Finally, speakers presented new technologies to interrogate the immune system and uncover novel metabolic pathways important for immunity. [ABSTRACT FROM AUTHOR]

Choices have consequences. Immune cells survey and migrate throughout the body and sometimes take residence in niche environments with distinct communities of cells, extracellular matrix, and nutrients that may differ from those in which they matured. Imbedded in immune cell physiology are metabolic pathways and metabolites that not only provide energy and substrates for growth and survival, but also instruct effector functions, differentiation, and gene expression. This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease. [ABSTRACT FROM AUTHOR]

Transforming growth factor β (TGFβ) is an important differentiation factor for cytotoxic T lymphocytes (CTLs) and alters the expression levels of several of homing receptors during infection. SMAD4 is part of the canonical signaling network used by members of the transforming growth factor family. For this study, genetically modified mice were used to determine how SMAD4 and TGFβ receptor II (TGFβRII) participate in transcriptional programming of pathogen-specific CTLs. We show that these molecules are essential components of opposing signaling mechanisms, and cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissues. TGFβ uses a canonical SMAD-dependent signaling pathway to downregulate Eomesodermin (EOMES), KLRG1, and CD62L, while CD103 is induced. Conversely, in vivo and in vitro data show that EOMES, KLRG1, CX3CR1, and CD62L are positively regulated via SMAD4, while CD103 and Hobit are downregulated. Intravascular staining also shows that signaling via SMAD4 promotes formation of long-lived terminally differentiated CTLs that localize in the vasculature. Our data show that inflammatory molecules play a key role in lineage determination of pathogen-specific CTLs, and use SMAD-dependent signaling to alter the expression levels of multiple homing receptors and transcription factors with known functions during memory formation. [ABSTRACT FROM AUTHOR]

Tissue-resident memory CD8 T cells are a unique subset of virus-specific CTLs that bolster local immune responses after becoming lodged in previously infected tissues. These cells provide enhanced protection by intercepting returning pathogens before a new infection gets established. In contrast, central memory CDS T cells circulate in the bloodstream and proliferate in secondary lymphoid organs before replenishing effector and memory CDS T cell populations in remote parts of the body. Both populations of virus-specific memory CDS T cells participate in immunity to influenza virus infection; however, the signaling pathways that instruct developing memory CDS T cells to distribute to specific tissues are poorly defined. We show that TGF-β promotes the development of pulmonary tissue-resident memory T cells via a signaling pathway that does not require the downstream signaling intermediate Sma- and Mad-related protein (Smad)4. In contrast, circulating memory CD8 T cells have no requirement for TGF-β but show signs of arrested development in the absence of Smad4, including aberrant CD103 expression. These signaling pathways alter the distribution of virus-specific CTLs in the lungs but do not prevent robust cytokine responses. Our data show that Smad4 is required for normal differentiation of multiple subsets of virus-specific CD8 T cells. In normal circumstances, Smad4 may be activated via a pathway that bypasses the TGF-β receptor. Improved understanding of these signaling pathways could be used to augment vaccine-induced immunity. [ABSTRACT FROM AUTHOR]

Tissue-resident memory CD8 T cells are a unique subset of virus-specific CTLs that bolster local immune responses after becoming lodged in previously infected tissues. These cells provide enhanced protection by intercepting returning pathogens before a new infection gets established. In contrast, central memory CD8 T cells circulate in the bloodstream and proliferate in secondary lymphoid organs before replenishing effector and memory CD8 T cell populations in remote parts of the body. Both populations of virus-specific memory CD8 T cells participate in immunity to influenza virus infection; however, the signaling pathways that instruct developing memory CD8 T cells to distribute to specific tissues are poorly defined. We show that TGF-β promotes the development of pulmonary tissue-resident memory T cells via a signaling pathway that does not require the downstream signaling intermediate Sma- and Mad-related protein (Smad)4. In contrast, circulating memory CD8 T cells have no requirement for TGF-β but show signs of arrested development in the absence of Smad4, including aberrant CD103 expression. These signaling pathways alter the distribution of virus-specific CTLs in the lungs but do not prevent robust cytokine responses. Our data show that Smad4 is required for normal differentiation of multiple subsets of virus-specific CD8 T cells. In normal circumstances, Smad4 may be activated via a pathway that bypasses the TGF-β receptor. Improved understanding of these signaling pathways could be used to augment vaccine-induced immunity. [ABSTRACT FROM AUTHOR]

Summary: Inducing memory CD8+ T cells specific for conserved antigens from influenza A virus (IAV) is a potential strategy for broadly protective vaccines. Here we show that memory CD8+ T cells in the airways played an important role in early control of IAV. Expression of the chemokine receptor CXCR3 was critical for memory CD8+ T cells to populate the airways during the steady state and vaccination approaches were designed to favor the establishment of memory CD8+ T cells in the airways. Specifically, we found that interleukin-12 (IL-12) signaling shortly after immunization limited CXCR3 expression on memory CD8+ T cells. Neutralization of IL-12 or adjuvants that did not induce high amounts of IL-12 enhanced CXCR3 expression, sustained airway localization of memory CD8+ T cells, and resulted in superior protection against IAV. [Copyright &y& Elsevier]

Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers. [Display omitted] • ARID1A loss is sufficient to induce anti-tumor immunity and immunotherapy response • ARID1A loss or cBAF inhibition induces interferon (IFN)-stimulated gene expression • ARID1A-IFN signature is driven by R-loop-derived cytosolic DNA and the STING pathway • ARID1A mutant anti-tumor immunity and immunotherapy response are type I IFN dependent ARID1A loss in tumor cells triggers anti-tumor immunity via R-loop-derived cytosolic DNA and activation of the STING-type I interferon pathway, defining a molecular mechanism underlying ARID1A mutant anti-tumor immunity and immunotherapy response observed clinically. [ABSTRACT FROM AUTHOR]

During an infection, T cells can differentiate into multiple types of effector and memory T cells, which help to mediate pathogen clearance and provide long-term protective immunity. These cells can vary in their phenotype, function and location, and in their long-term fate in terms of their ability to populate the memory T cell pool. Over the past decade, the signalling pathways and transcriptional programmes that regulate the formation of heterogeneous populations of effector and memory CD8(+) T cells have started to be characterized, and this Review discusses the major advances in these areas. [ABSTRACT FROM AUTHOR]

Abstract: The quantity and activity of mitochondria vary dramatically in tissues and are modulated in response to changing cellular energy demands and environmental factors. The amount of mitochondrial DNA (mtDNA), which encodes essential subunits of the oxidative phosphorylation complexes required for cellular ATP production, is also tightly regulated, but by largely unknown mechanisms. Using murine T cells as a model system, we have addressed how specific signaling pathways influence mitochondrial biogenesis and mtDNA copy number. T cell receptor (TCR) activation results in a large increase in mitochondrial mass and membrane potential and a corresponding amplification of mtDNA, consistent with a vital role for mitochondrial function for growth and proliferation of these cells. Independent activation of protein kinase C (via PMA) or calcium-related pathways (via ionomycin) had differential and sub-maximal effects on these mitochondrial parameters, as did activation of naïve T cells with proliferative cytokines. Thus, the robust mitochondrial biogenesis response observed upon TCR activation requires synergy of multiple downstream signaling pathways. One such pathway involves AMP-activated protein kinase (AMPK), which we show has an unprecedented role in negatively regulating mitochondrial biogenesis that is mammalian target of rapamycin (mTOR)-dependent. That is, inhibition of AMPK after TCR signaling commences results in excessive, but uncoordinated mitochondrial proliferation. Thus mitochondrial biogenesis is not under control of a single master regulatory circuit, but rather requires the convergence of multiple signaling pathways with distinct downstream consequences on the organelle’s structure, composition, and function. [Copyright &y& Elsevier]

Summary: Chronic viral infections often result in T cell exhaustion. To determine the molecular signature of exhaustion, we compared the gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells from chronic infection to functional LCMV-specific effector and memory CD8+ T cells generated after acute infection. These data showed that exhausted CD8+ T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and cytokine signaling pathways, (3) displayed altered expression of genes involved in chemotaxis, adhesion, and migration, (4) expressed a distinct set of transcription factors, and (5) had profound metabolic and bioenergetic deficiencies. T cell exhaustion was progressive, and gene-expression profiling indicated that T cell exhaustion and anergy were distinct processes. Thus, functional exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections. [Copyright &y& Elsevier]

During many acute viral and bacterial infections, IL-7 receptor α-chain (IL-7Rα) is expressed on a subset of effector CD8 T cells that preferentially develop into long-lived memory CD8 T cells. These cells functionally require IL-7Rα, but it is unclear whether IL-7Rα acts mainly to induce their differentiation into memory cells or to sustain their long-term survival. To examine this question, IL-7Rα was constitutively overexpressed on alt antigen-specific effector CD8 T cells during viral infection. Constitutive IL-7Rα expression had minimal effects on the numbers or function of effector and memory CD8 T cells formed. This indicated that IL-7Rα expression is not sufficient to drive memory cell development. In particular, the forced IL-7Rα expression did not rescue the killer cell lectin-like receptor Gi (KLRG1)hi short-lived effector CD8 T cells from death, showing that the majority of effector CD8 T cells die in an IL-7Rα-independent manner. Moreover, we found that, regardless of the ectopic expression of IL-7Rα, the KLRG1hi but not the KLRG1lo effector CD8 T cells, were unable to proliferate well to IL-7, which may be due to increased amounts of p27kip in KLRG1hi cells. Because lL-7 can destabilize p27kip, this result suggested that KLRG1hi and KLRG1lo effector CD8 T cells naturally differ in their ability to transmit IL-7 signals. Altogether, these results reveal that IL-7Rα expression is permissive, but not instructive, to the creation of memory CD8 T cells. [ABSTRACT FROM AUTHOR]

Memory I cells can persist for extended periods in the absence of antigen, and long-term T cell immunity is often seen after acute infections. Paradoxically, there have been observations suggesting that T cell memory may be antigen-dependent during chronic infections. To elucidate the underlying mechanisms we have compared memory CD8 T cell differentiation during an acute versus chronic infection by using the mouse model of infection with lymphocytic choriomeningitis virus. We found that during a chronic infection virus-specific CD8 T cells failed to acquire the cardinal memory T cell property of long-term antigen-independent persistence. These chronically stimulated CDS T cells were unable to undergo homeostatic proliferation, responded poorly to IL-7 and 11-15, and expressed reduced levels of the 11-7 and 11-15 receptors, thus providing a possible mechanism for the inability of these cells to persist long term in the absence of antigen. In striking contrast, virus-specific memory CD8 T cells that developed after an acute lymphocytic choriomeningitis virus infection could persist without antigen, were capable of self-renewal because of homeostatic proliferation, responded efficiently to IL-7 and IL-15, and expressed high levels of receptors for these two cytokines. Thus, memory CD8 T cells generated after acute infections are likely to have a competitive advantage over CDS T cells that develop during chronic infections. These findings raise concerns about using vaccines that may persist and also suggest that there may be limitations and challenges in designing effective immunological interventions for the treatment of chronic infections and tumors. [ABSTRACT FROM AUTHOR]

Improved understanding of host antiviral defense and antitumor immunity have elucidated molecular pathways important to both processes. During viral infection, RNA or DNA in the host cell serves as a danger signal that initiates the antiviral response. Recent studies have elucidated similarities in the signaling pathways activated by viruses and the signaling pathways induced by tumor DNA that is released into the cytoplasm of irradiated tumor cells. Both the host defense to viral infection and the sterile inflammation provoked by radiotherapy induce a type I interferon response that is necessary for pathogen control and immune-mediated tumor control, respectively. These findings have led to the hypothesis that radiotherapy employs a form of viral mimicry. [ABSTRACT FROM AUTHOR]

In the direct competition for metabolic resources between cancer cells and tumor-infiltrating CD8+ T cells, the latter are bound to lose out. These effector lymphocytes are therefore rendered exhausted or dysfunctional. Emerging insights into the mechanisms of T cell unresponsiveness in the tumor microenvironment (TME) point towards epigenetic mechanisms as crucial regulatory factors. In this review, we discuss the effects of characteristic components of the TME, i.e. glucose/amino acid dearth with elevated levels of reactive oxygen species (ROS), on DNA methylation and histone modifications in CD8+ T cells. We then take a closer look at the translational potential of epigenetic interventions that aim to improve current immunotherapeutic strategies, including the adoptive transfer of T cell receptor (TCR) or chimeric antigen receptor (CAR) engineered T cells. The tumor microenvironment forms a metabolic barrier against cytotoxic CD8+ T cells, thus hampering current immunotherapeutic strategies. It is increasingly recognized that epigenetics bridges cellular metabolism with gene expression. Tackling epigenetic modifications or cell metabolism to (i) target the epigenetic signature of (tumor-infiltrating) CD8+ T cells in vivo , or (ii) potentiate the ex vivo generation of antitumor T cell grafts for adoptive cell transfer, has gained much interest as a promising strategy to combat malignancy. [ABSTRACT FROM AUTHOR]

The seasonal influenza vaccine is an important public health tool but is only effective in a subset of individuals. The identification of molecular signatures provides a mechanism to understand the drivers of vaccine-induced immunity. Most previously reported molecular signatures of human influenza vaccination were derived from a single age group or season, ignoring the effects of immunosenescence or vaccine composition. Thus, it remains unclear how immune signatures of vaccine response change with age across multiple seasons. In this study we profile the transcriptional landscape of young and older adults over five consecutive vaccination seasons to identify shared signatures of vaccine response as well as marked seasonal differences. Along with substantial variability in vaccine-induced signatures across seasons, we uncovered a common transcriptional signature 28 days postvaccination in both young and older adults. However, gene expression patterns associated with vaccine-induced Ab responses were distinct in young and older adults; for example, increased expression of killer cell lactin-like receptor B1 (KLRB1; CD161) 28 days postvaccination positively and negatively predicted vaccine-induced Ab responses in young and older adults, respectively. These findings contribute new insights for developing more effective influenza vaccines, particularly in older adults. [ABSTRACT FROM AUTHOR]

CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states. [Display omitted] • ARID1A-containing cBAF opens enhancers in effector CD8+ T cells during infection • cBAF establishes binding sites of many effector TFs, including T-bet and BATF • cBAF is necessary for late-stage differentiation of TE and Trm cells • Circulating memory cells form without cBAF, but are functionally impaired Chromatin remodeling is a critical step for cellular differentiation. McDonald et al. show that the canonical BAF complex mediates chromatin remodeling to establish de novo enhancers in recently activated virus-specific CD8+ T cells, which, in turn, allows the activated cells to acquire specialized effector and memory cell fates. [ABSTRACT FROM AUTHOR]

Virus infections induce CD8+ T cell responses comprised of a large population of terminal effector cells and a smaller subset of long-lived memory cells. The transcription factors regulating the relative expansion versus the long-term survival potential of anti-viral CD8+ T cells are not completely understood. We identified ZBTB32 as a transcription factor that is transiently expressed in effector CD8+ T cells. After acute virus infection, CD8+ T cells deficient in ZBTB32 showed enhanced virus-specific CD8+ T cell responses, and generated increased numbers of virus-specific memory cells; in contrast, persistent expression of ZBTB32 suppressed memory cell formation. The dysregulation of CD8+ T cell responses in the absence of ZBTB32 was catastrophic, as Zbtb32-/- mice succumbed to a systemic viral infection and showed evidence of severe lung pathology. We found that ZBTB32 and Blimp-1 were co-expressed following CD8+ T cell activation, bound to each other, and cooperatively regulated Blimp-1 target genes Eomes and Cd27. These findings demonstrate that ZBTB32 is a key transcription factor in CD8+ effector T cells that is required for the balanced regulation of effector versus memory responses to infection. [ABSTRACT FROM AUTHOR]

Summary Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naive, MP, and TE CD8 + T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro-effector genes in MP cells, indicative of multipotency. Polycomb repressive complex 2 deficiency impaired clonal expansion and TE cell differentiation, but minimally impacted CD8 + memory T cell maturation. Abundant H3K27me3 deposition at pro-memory genes occurred late during TE cell development, probably from diminished transcription factor FOXO1 expression. These results outline a temporal model for loss of memory cell potential through selective epigenetic silencing of pro-memory genes in effector T cells. [ABSTRACT FROM AUTHOR]

Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle. Moreover, in histone 2B-GFP mice, the 2B-GFP label was retained in Tsp cells, indicative of a slow-cycling phenotype. Human Tsp cells displayed a distinct gene-expression profile that was enriched for genes overexpressed in Trm cells. In mice, proteins encoded by Tsp signature genes, including nuclear receptor subfamily 4 group A member 1 (NR4A1) and ATP-binding cassette (ABC) transporters, influenced the function and differentiation of Trm cells. Responses to adoptive transfer of human Tsp cells into immune-deficient mice and plerixafor therapy suggested that human Tsp cell mobilization could be manipulated as a potential cellular therapy. These data identify a distinct subset of human T cells with a quiescent/slow-cycling phenotype, propensity for tissue enrichment, and potential to mobilize into circulation, which may be harnessed for adoptive cellular therapy. [ABSTRACT FROM AUTHOR]

C-C receptor 7 (CCR7) is important to allow T cells and dendritic cells to migrate toward CCL19- and CCL21-producing cells in the T-cell zone of the spleen and lymph nodes. The role of this chemokine receptor in regulating the homeostasis of effector and memory T cells during acute viral infection is poorly defined, however. In this study, we show that CCR7 expression alters memory CD8 T-cell homeostasis following lymphocytic choriomeningitis virus infection. Greater numbers of CCR7-deficient memory T cells were formed and maintained compared with CCR7-sufficient memory T cells, especially in the lung and bone marrow. The CCR7-deficient memory T cells also displayed enhanced rates of homeostatic turnover, which may stem from increased exposure to IL-15 as a consequence of reduced exposure to IL-7, because removal of IL-15, but not of IL-7, normalized the numbers of CCR7-sufficient and CCR7-deficient memory CD8 T cells. This result suggests that IL-15 is the predominant cytokine supporting augmentation of the CCR7-/- memory CD8 T-cell pool. Taken together, these data suggest that CCR7 biases memory CD8 T cells toward IL-7-dependent niches over IL-15- dependent niches, which provides insight into the homeostatic regulation of different memory T-cell subsets. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus is caused by the killing of insulinproducing β cells by CD8+T cells. The disease progression, which is chronic, does not follow a course like responses to conventional antigens such as viruses, but accelerates as glucose tolerance deteriorates. To identify the unique features of the autoimmune effectors that may explain this behavior, we analyzed diabetogenic CD8+ T cells that recognize a peptide from the diabetes antigen IGRP (NRP-V7-reactive) in prediabetic NOD mice and compared them to others that shared their phenotype (CD44+CD62LIoPD-1+CXCR3+) but negative for diabetes antigen tetramers and to LCMV (lymphocytic choriomeningitis)- reactive CD8+ T cells. There was an increase in the frequency of the NRP-V7-reactive cells coinciding with the time of glucose intolerance. The T cells persisted in hyperglycemic NODmice maintained with an insulin pellet despite destruction of β cells. We compared gene expression in the three groups of cells compared with the other two subsets of cells, and the NRPV7- reactive cells exhibited gene expression of memory precursor effector cells. They had reduced cellular proliferation and were less dependent on oxidative phosphorylation. When prediabetic NOD mice were treated with 2-deoxyglucose to block aerobic glycolysis, there was a reduction in the diabetes antigen versus other cells of similar phenotype and loss of lymphoid cells infiltrating the islets. In addition, treatment of NOD mice with 2-deoxyglucose resulted in improved β cell granularity. These findings identify a link between metabolic disturbances and autoreactive T cells that promotes development of autoimmune diabetes. [ABSTRACT FROM AUTHOR]