Search

Summary: Upon resolution of an acute viral infection, during latent‐reactivating infection and during chronic active infections virus‐specific T‐cells differentiate into distinct subsets that differ in phenotype, longevity, transcriptional, metabolic, and epigenetic profiles, and effector functions. With recent advances in single‐cell profiling, this substantial heterogeneity has become apparent and new subsets of virus‐specific T cells, either of stable or transitory nature, are being identified. A unifying principle of T cells emerging in these different conditions is their precursor–progeny relationship. For acute and resolved viral infections, this relationship becomes apparent during re‐challenge, whereas a constant differentiation of progenitor T cells into more differentiated cells occurs during latent‐reactivating and active chronic viral infections. In this review, we summarize and discuss current knowledge about T‐cell heterogeneity and progenitor–progeny relationships in the setting of persistent viral infections. [ABSTRACT FROM AUTHOR]

The lymph node plays a critical role in mounting an adaptive immune response to infection, clearance of foreign pathogens, and cancer immunosurveillance. Within this complex structure, intranodal migration is vital for CD8+ T cell activation and differentiation. Combining tissue clearing and volumetric light sheet fluorescent microscopy of intact lymph nodes has allowed us to explore the spatial regulation of T cell fates. This has determined that short‐lived effector (TSLEC) are imprinted in peripheral lymph node interfollicular regions, due to CXCR3 migration. In contrast, stem‐like memory cell (TSCM) differentiation is determined in the T cell paracortex. Here, we detail the inflammatory and chemokine regulators of spatially restricted T cell differentiation, with a focus on how to promote TSCM. We propose a default pathway for TSCM differentiation due to CCR7‐directed segregation of precursors away from the inflammatory effector niche. Although volumetric imaging has revealed the consequences of intranodal migration, we still lack knowledge of how this is orchestrated within a complex chemokine environment. Toward this goal, we highlight the potential of combining microfluidic chambers with pre‐determined complexity and subcellular resolution microscopy. [ABSTRACT FROM AUTHOR]

Following antigen recognition, CD8+ T lymphocytes can follow different patterns of differentiation, with the generation of different subsets characterized by distinct phenotypes, functions, and migration properties. The changes of transcription factors activity and chromatin structure dynamics drive the functional differentiation and phenotypic heterogeneity of these T cell subsets, which include short‐lived effectors, long‐term survival of memory, and also dysfunctional exhausted T cells. Recent progress in the field has shed light on the key contribution of chromatin organization to control the T cell fate specification. In fact, the understanding of these processes has important implications for the development of new immunotherapy protocols and to design new vaccination strategies. Here, we review the current understanding of the contribution of chromatin architecture and transcription factor activity orchestrating the gene expression programs guiding the CD8+ T cell subset commitment. We will focus on epigenetic changes, acting sequentially or in combination, which control the transcriptional programs governing T cell plasticity, stability, and memory. New molecular insights into the mechanisms of maintenance of cellular memory and identity, favoring or impeding the reprogramming, will be discussed in the context of T cell memory differentiation in infection and cancer. [ABSTRACT FROM AUTHOR]

T cell homeostasis, T cell differentiation, and T cell effector function rely on the constant fine‐tuning of gene expression. To alter the T cell state, substantial remodeling of the proteome is required. This remodeling depends on the intricate interplay of regulatory mechanisms, including post‐transcriptional gene regulation. In this review, we discuss how the sequence of a transcript influences these post‐transcriptional events. In particular, we review how sequence determinants such as sequence conservation, GC content, and chemical modifications define the levels of the mRNA and the protein in a T cell. We describe the effect of different forms of alternative splicing on mRNA expression and protein production, and their effect on subcellular localization. In addition, we discuss the role of sequences and structures as binding hubs for miRNAs and RNA‐binding proteins in T cells. The review thus highlights how the intimate interplay of post‐transcriptional mechanisms dictate cellular fate decisions in T cells. [ABSTRACT FROM AUTHOR]

The relationship between the extrinsic environment and the internal transcriptional network is circular. Naive T cells first engage with antigen‐presenting cells to set transcriptional differentiation networks in motion. In turn, this regulates specific chemokine receptors that direct migration into distinct lymph node niches. Movement into these regions brings newly activated T cells into contact with accessory cells and cytokines that reinforce the differentiation programming to specify T cell function. We and others have observed similarities in the transcriptional networks that specify both CD4+ T follicular helper (TFH) cells and CD8+ central memory stem‐like (TSCM) cells. Here, we compare and contrast the current knowledge for these shared differentiation programs, compared to their effector counterparts, CD4+ T‐helper 1 (TH1) and CD8+ short‐lived effector (TSLEC) cells. Understanding the interplay between cellular interactions and transcriptional programming is essential to harness T cell differentiation that is fit for purpose; to stimulate potent T cell effector function for the elimination of chronic infection and cancer; or to amplify the formation of humoral immunity and longevity of cellular memory to prevent infectious diseases. [ABSTRACT FROM AUTHOR]

The conceptualization of adaptive immunity, founded on the observation of immunological memory, has served as the basis for modern vaccination and immunotherapy approaches. This fundamental concept has allowed immunologists to explore mechanisms that enable humoral and cellular lymphocytes to tailor immune response functions to a wide array of environmental insults and remain poised for future pathogenic encounters. Until recently, for T cells it has remained unclear how memory differentiation acquires and sustains a gene expression program that grants a cell with a capacity for a heightened recall response. Recent investigations into this critical question have identified epigenetic programs as a causal molecular mechanism governing T cell subset specification and immunological memory. Here, we outline the studies that have illustrated this concept and posit on how insights into T cell adaptive immunity can be applied to improve upon existing immunotherapies. [ABSTRACT FROM AUTHOR]

Antibody‐secreting cells (ASCs) or plasma cells secrete antibodies and form a cornerstone of humoral immunity. B cells that receive activation signals in the presence or absence of T cells initiate a differentiation program that requires epigenetic and transcriptional reprogramming in order to ultimately form ASC. Reprogramming is accomplished through the interplay of transcription factors that initiate gene expression programs and epigenetic mechanisms that maintain these programs and cell fates. An important consideration is that all of these factors are operating in the context of cell division. Recent technical advances now allow mechanistic studies to move beyond genetic studies to identify the promoters and enhancer repertoires that are regulated by epigenetic mechanisms and transcription factors in rare cell types and differentiation stages in vivo. This review will detail efforts to integrate transcriptional and epigenetic changes during B cell differentiation with cell division in vivo. What has emerged is a multiphased differentiation model that requires distinct transcription factors and epigenetic programs at each step. The identification of markers that define each phase will help facilitate the manipulation of B cell differentiation for vaccine development or to treat diseases where antibodies are a component. [ABSTRACT FROM AUTHOR]

The contributions of γδ T cells to immune (patho)physiology in many pre‐clinical mouse models have been associated with their rapid and abundant provision of two critical cytokines, interferon‐γ (IFN‐γ) and interleukin‐17A (IL‐17). These are typically produced by distinct effector γδ T cell subsets that can be segregated on the basis of surface expression levels of receptors such as CD27, CD44 or CD45RB, among others. Unlike conventional T cells that egress the thymus as naïve lymphocytes awaiting further differentiation upon activation, a large fraction of murine γδ T cells commits to either IFN‐γ or IL‐17 expression during thymic development. However, extrathymic signals can both regulate pre‐programmed γδ T cells; and induce peripheral differentiation of naïve γδ T cells into effectors. Here we review the key cellular events of "developmental pre‐programming" in the mouse thymus; and the molecular basis for effector function maintenance vs plasticity in the periphery. We highlight some of our contributions towards elucidating the role of T cell receptor, co‐receptors (like CD27 and CD28) and cytokine signals (such as IL‐1β and IL‐23) in these processes, and the various levels of gene regulation involved, from the chromatin landscape to microRNA‐based post‐transcriptional control of γδ T cell functional plasticity. [ABSTRACT FROM AUTHOR]

In rheumatoid arthritis (RA), breakdown of self‐tolerance and onset of clinical disease are separated in time and space, supporting a multi‐hit model in which emergence of autoreactive T cells is a pinnacle pathogenic event. Determining factors in T cell differentiation and survival include antigen recognition, but also the metabolic machinery that provides energy and biosynthetic molecules for cell building. Studies in patients with RA have yielded a disease‐specific metabolic signature, which enables naive CD4 T cells to differentiate into pro‐inflammatory helper T cells that are prone to invade into tissue and elicit inflammation through immunogenic cell death. A typifying property of RA CD4 T cells is the shunting of glucose away from glycolytic breakdown and mitochondrial processing toward the pentose phosphate pathway, favoring anabolic over catabolic reactions. Key defects have been localized to the mitochondria and the lysosome; including instability of mitochondrial DNA due to the lack of the DNA repair nuclease MRE11A and inefficient lysosomal tethering of AMPK due to deficiency of N‐myristoyltransferase 1 (NMT1). The molecular taxonomy of the metabolically reprogrammed RA T cells includes glycolytic enzymes (glucose‐6‐phosphate dehydrogenase, phosphofructokinase), DNA repair molecules (MRE11A, ATM), regulators of protein trafficking (NMT1), and the membrane adapter protein TSK5. As the mechanisms determining abnormal T cell behavior in RA are unraveled, opportunities will emerge to interject autoimmune T cells by targeting their metabolic checkpoints. [ABSTRACT FROM AUTHOR]

Summary: The initiation of T lymphocyte responses within secondary lymphoid organs involves interactions with different subsets of dendritic cells (DCs). Recent studies have revealed the complexity of microanatomical organization within lymphoid organs. Exactly how T cells and DCs locate each other and the type of cellular interactions required for optimal priming of effector and memory T cell responses are beginning to be unraveled. Here we review advances in our understanding of how T cell priming is choreographed during infections, highlight the importance of cell positioning in this process and discuss how a spectrum of cellular interactions shapes T cell activation and differentiation. [ABSTRACT FROM AUTHOR]

Summary: A fundamental question in immunology is how cells decide between distinct T helper, effector or memory differentiation fates. These decisions are paramount to overcome infection and establish long‐lasting protection. The impact of cell location for the determination of T‐cell fate decisions is an emerging field. This review will discuss our current understanding of the migration path that T cells follow, within draining lymph nodes, to steer differentiation down distinct paths of either effector or memory fates. In particular, the regulation of migration and cellular encounters mediated by the chemokine receptor CXCR3 and its ligands will be discussed. The combination of increased antigen density and unique cellular partners play a central role in facilitating the site‐specific differentiation of effector T cells, within the interfollicular regions of draining lymph nodes. Recent advances have applied this knowledge to optimize vaccine design to target antigen to lymph nodes. Increased understanding of the regulation of CXCR3 ligands and how T cells integrate multiple chemokine cues will help further progress in this field and allow additional applications to direct cell differentiation outside the lymph node, to enhance memory residency in peripheral tissues and effector anti‐tumor responses. [ABSTRACT FROM AUTHOR]

Summary: T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class‐switch recombination, and generation of long‐lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naive CD4+ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh‐like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets. [ABSTRACT FROM AUTHOR]

Summary: Upon stimulation with their cognate antigen, naive T cells undergo proliferation and differentiation into effector cells, followed by apoptosis or survival as precursors of long‐lived memory cells. These phases of a T‐cell response and the ensuing maintenance of memory T cells are shaped by cytokines, most notably interleukin‐2 (IL‐2), IL‐7, and IL‐15 that share the common γ chain (γc) cytokine receptor. Steady‐state production of IL‐7 and IL‐15 is necessary for background proliferation and homeostatic survival of CD4+ and CD8+ memory T cells. During immune responses, augmented levels of IL‐2, IL‐15, IL‐21, IL‐12, IL‐18, and type‐I interferons determine the memory potential of antigen‐specific effector CD8+ cells, while increased IL‐2 and IL‐15 cause bystander proliferation of heterologous CD4+ and CD8+ memory T cells. Limiting availability of γc cytokines, reduction in regulatory T cells or IL‐10, and persistence of inflammation or cognate antigen can result in memory T cells, which fail to become cytokine‐dependent long‐lived cells. Conversely, increased IL‐7 and IL‐15 can expand memory T cells, including pathogenic tissue‐resident memory T cells, as seen in lymphopenia and certain chronic‐inflammatory disorders and malignancies. These abovementioned factors impact immunotherapy and vaccines directed at memory T cells in cancer and chronic infection. [ABSTRACT FROM AUTHOR]

An estimated 300 million people currently suffer from asthma, which causes approximately 250 000 deaths a year. Allergen-specific T-helper (Th) cells produce cytokines that induce many of the hallmark features of asthma including airways hyperreactivity, eosinophilic and neutrophilic inflammation, mucus hypersecretion, and airway remodeling. Cytokine-producing Th subsets including Th1 ( IFN-γ), Th2 ( IL-4, IL-5, IL-13), Th9 ( IL-9), Th17 ( IL-17), Th22 ( IL-22), and T regulatory ( IL-10) cells have all been suggested to play a role in the development of asthma. Th differentiation involves genetic regulation of gene expression through the concerted action of cytokines, transcription factors, and epigenetic regulators. We describe how Th differentiation and plasticity is regulated by epigenetic histone and DNA modifications, with a focus on the regulation of histone methylation by members of the polycomb and trithorax complexes. In addition, we outline environmental influences that could influence epigenetic regulation of Th cells and discuss the potential to regulate Th plasticity and function through drugs targeting the epigenetic machinery. It is also becoming apparent that epigenetic regulation of allergen-specific memory Th cells may be important in the development and persistence of chronic allergies. Finally, we describe how epigenetic modifiers regulate cytokine memory in Th cells and describe recently identified hybrid, plastic, and pathogenic memory Th subsets the context of allergic asthma. [ABSTRACT FROM AUTHOR]

Itch or itchy E3 ubiquitin ligase was initially discovered by genetic studies on the mouse coat color changes, and its deletion results in an itchy phenotype with constant skin scratching and multi-organ inflammation. It is a member of the homologous to E6-associated protein C-terminus ( HECT)-type family of E3 ligases, with the protein-interacting WW-domains for the recruitment of substrate and the HECT domain for the transfer of ubiquitin to the substrate. Since its discovery, numerous studies have demonstrated that Itch is involved in the control of many aspects of immune responses including T-cell activation and tolerance and T-helper cell differentiation. Itch is also implicated in other biological contexts such as tumorigenesis, development, and stress responses. Many signaling pathways are regulated by Itch-promoted ubiquitylation of diverse target proteins. Itch is also involved in human diseases. Here, we discuss the major progress in understanding the biological significance of Itch-promoted protein ubiquitylation in the immune and other systems and in Itch-mediated regulation of signal transduction. [ABSTRACT FROM AUTHOR]

Much progress has been made toward understanding the mechanistic basis of transplantation tolerance in experimental models, which implicates clonal deletion of alloreactive T and B cells, induction of cell-intrinsic hyporesponsiveness, and dominant regulatory cells mediating infectious tolerance and linked suppression. Despite encouraging success in the laboratory, achieving tolerance in the clinic remains challenging, although the basis for these challenges is beginning to be understood. Heterologous memory alloreactive T cells generated by infections prior to transplantation have been shown to be a critical barrier to tolerance induction. Furthermore, infections at the time of transplantation and tolerance induction provide a pro-inflammatory milieu that alters the stability and function of regulatory T cells as well as the activation requirements and differentiation of effector T cells. Thus, infections can result in enhanced alloreactivity, resistance to tolerance induction, and destabilization of the established tolerance state. We speculate that these experimental findings have relevance to the clinic, where infections have been associated with allograft rejection and may be a causal event precipitating the loss of grafts after long periods of stable operational tolerance. Understanding the mechanisms by which infections prevent and destabilize tolerance can lead to therapies that promote stable life-long tolerance in transplant recipients. [ABSTRACT FROM AUTHOR]

Post-transcriptional gene regulation by RNA-binding proteins is a fast and effective way to adapt gene expression and change cellular responses. These trans-acting factors have been involved in a number of cell fate decisions, and their mutation is often associated with the development of disease. The RNA-binding protein Roquin-1 has been found to be crucial in the maintenance of peripheral tolerance and the prevention of autoimmune disease. This review describes the molecular role of Roquin family proteins in the control of follicular T-helper cell differentiation. Here, we discuss the redundant regulation of Icos and Ox40 costimulatory receptor mRNAs by Roquin-1 and Roquin-2 proteins. A major focus is placed on the distinct activity of Roquin-1 or Roquin-2 proteins in the mouse models of conditional gene targeting. These recent data are then integrated into an interpretation of altered Roquin protein function in the sanroque mouse that expresses the Roquin-1 protein with just one amino acid substitution and, different from the Roquin-1-deficient mouse, develops lupus-like autoimmune disease. [ABSTRACT FROM AUTHOR]

Discovery of the T-helper 17 (Th17) subset heralded a major shift in T-cell biology and immune regulation. In addition to defining a new arm of the adaptive immune response, studies of the Th17 pathway have led to a greater appreciation of the developmental flexibility, or plasticity, that is a feature of T-cell developmental programs. Since the initial finding that differentiation of Th17 cells is promoted by transforming growth factor-β ( TGFβ), it became clear that Th17 cell development overlapped that of induced regulatory T (iTreg) cells. Subsequent findings established that Th17 cells are also unusually flexible in their late developmental programming, demonstrating substantial overlap with conventional Th1 cells through mechanisms that are just beginning to be understood but would appear to have important implications for immunoregulation at homeostasis and in immune-mediated diseases. Herein we examine the developmental and functional features of Th17 cells in relation to iTreg cells, Th1 cells, and Th22 cells, as a basis for understanding the contributions of this pathway to host defense, immune homeostasis, and immune-mediated disease. [ABSTRACT FROM AUTHOR]

CD4+ T-helper cells regulate immunity and inflammation through the acquisition of potential to secrete specific cytokines. The acquisition of cytokine-secreting potential, in a process termed T-helper cell differentiation, is a response to multiple environmental signals including the cytokine milieu. The most recently defined subset of T-helper cells are termed Th9 and are identified by the potent production of interleukin-9 ( IL-9). Given the pleiotropic functions of IL-9, Th9 cells might be involved in pathogen immunity and immune-mediated disease. In this review, I focus on recent developments in understanding the signals that promote Th9 differentiation, the transcription factors that regulate IL-9 expression, and finally the potential roles for Th9 cells in immunity in vivo. [ABSTRACT FROM AUTHOR]

Intestinal CD4+ T cells are essential mediators of immune homeostasis and inflammation. Multiple subsets of CD4+ T cells have been described in the intestine, which represents an important site for the generation and regulation of cells involved in immune responses both within and outside of the gastrointestinal tract. Recent advances have furthered our understanding of the biology of such cells in the intestine. Appreciation of the functional roles for effector and regulatory populations in health and disease has revealed potential translational targets for the treatment of intestinal diseases, including inflammatory bowel disease. Furthermore, the role of dietary and microbiota-derived factors in shaping the intestinal CD4+ T-cell compartment is becoming increasingly understood. Here, we review recent advances in understanding the multifaceted roles of CD4+ T cells in intestinal immunity. [ABSTRACT FROM AUTHOR]

T-follicular helper (Tfh) cells are a new subset of effector CD4+ T cells that are specialized in helping B cells in the germinal center reaction. Tfh cells are distinct from other established CD4+ T-cell lineages, Th1, Th2, Th17, and T-regulatory cells, in their gene expression profiles. Tfh cell differentiation results from a network of transcriptional regulation by a master transcriptional factor Bcl6 as well as IRF4, c-Maf, Batf, and STAT3/5. During Tfh cell ontogeny, increased CXCR5 expression directs activated T-cell migration to the follicles, and their interaction with B cells leads to Bcl6 upregulation, which helps establish effector and memory Tfh cell program. This review summarizes the recent progress in molecular mechanisms underlying Tfh differentiation and discusses the future perspectives for this important area of research. [ABSTRACT FROM AUTHOR]

The interplay of the immune system with other aspects of physiology is continually being revealed and in some cases studied in considerable mechanistic detail. A prime example is the influence of metabolic cues on immune responses. It is well appreciated that upon activation, T cells take on a metabolic profile profoundly distinct from that of their quiescent and anergic counterparts; however, a number of recent breakthroughs have greatly expanded our knowledge of how aspects of cellular metabolism can shape a T-cell response. Particularly important are findings that certain environmental cues can tilt the delicate balance between inflammation and immune tolerance by skewing T-cell fate decisions toward either the T-helper 17 (Th17) or T-regulatory (Treg) cell lineage. Recognizing the unappreciated immune-modifying potential of metabolic factors and particularly those involved in the generation of these functionally opposing T-cell subsets will likely add new and potent therapies to our repertoire for treating immune mediated pathologies. In this review, we summarize and discuss recent findings linking certain metabolic pathways, enzymes, and by-products to shifts in the balance between Th17 and Treg cell populations. These advances highlight numerous opportunities for immune modulation. [ABSTRACT FROM AUTHOR]

Upon activation, quiescent naive T cells undergo a growth phase followed by massive clonal expansion and differentiation that are essential for appropriate immune defense and regulation. Accumulation of cell biomass during the initial growth and rapid proliferation during the expansion phase is associated with dramatically increased bioenergetic and biosynthetic demands. This not only requires a metabolic rewiring during the transition between resting and activation but also 'addicts' active T cells to certain metabolic pathways in ways that naive and memory T cells are not. We consider such addiction in terms of the biological effects of deprivation of metabolic substrates or inhibition of specific pathways in T cells. In this review, we illustrate the relevant metabolic pathways revealed by recent metabolic flux analysis and discuss the consequences of metabolic intervention on specific metabolic pathways in T lymphocytes. [ABSTRACT FROM AUTHOR]

Clearance or control of pathogens or tumors usually requires T-cell-mediated immunity. As such, understanding the mechanisms that govern the function, maintenance, and persistence of T cells will likely lead to new treatments for controlling disease. During an immune response, T-cell development is marked by striking changes in metabolism. There is a growing appreciation that these metabolic changes underlie the capacity of T cells to perform particular functions, and this has led to a recent focus on the idea that the manipulation of cellular metabolism can be used to shape adaptive immune responses. Although interest in this area has grown in the last few years, a full understanding of the metabolic control of T-cell functions, particularly during an immune response in vivo, is still lacking. In this review, we first provide a basic overview of metabolism in T cells, and then we focus on recent studies providing new or updated insights into the regulation of metabolic pathways and how they underpin T-cell differentiation and memory T-cell development. [ABSTRACT FROM AUTHOR]

When T cells encounter foreign antigen and appropriate costimulatory signals from professional antigen-presenting cells ( APCs), they initiate a coordinated program of rapid proliferation and differentiation, leading to the development of activated T cells with specific effector functions tailored toward pathogen clearance or control. One of the fundamental programs that underpin T-cell proliferation and function is the regulation of cellular metabolism. Recent efforts to identify the signal transduction pathways that regulate T-cell metabolism have led to the identification of liver kinase B1 ( LKB1) and AMP-activated protein kinase ( AMPK) as key regulators of T-cell metabolism. LKB1 and AMPK are part of an evolutionarily conserved signal transduction pathway that monitors cellular energy status. AMPK senses bioenergetic fluctuations in cells and works in concert with LKB1 to maintain cellular energy homeostasis by promoting catabolic pathways of ATP production and limiting processes that consume ATP. Recent data indicate that LKB1 and AMPK can influence diverse aspects of T-cell biology beyond metabolism, including T-cell development, peripheral T-cell homeostasis, and T-cell effector function. In this review, we focus on the regulation of lymphocyte metabolism by this energy-sensing pathway and discuss its influence on T-cell function. [ABSTRACT FROM AUTHOR]

Upon antigen recognition, naive T cells undergo rapid expansion and activation. The energy requirements for this expansion are formidable, and T-cell activation is accompanied by dramatic changes in cellular metabolism. Furthermore, the outcome of antigen engagement is guided by multiple cues derived from the immune microenvironment. Mammalian target of rapamycin ( mTOR) is emerging as a central integrator of these signals playing a critical role in driving T-cell differentiation and function. Indeed, multiple metabolic programs are controlled by mTOR signaling. In this review, we discuss the role of mTOR in regulating metabolism and how these pathways intersect with the ability of mTOR to integrate cues that guide the outcome of T-cell receptor engagement. [ABSTRACT FROM AUTHOR]

Summary: Although the diverse functions served by the nuclear factor-κB (NF-κB) pathway in virtually all cell types are typically employed to deal with stress responses, NF-κB transcription factors also play key roles in the development of hemopoietic cells. This review focuses on how NF-κB transcription factors control various aspects of thymic T-cell and myeloid cell differentiation that include its roles in hemopoietic precursors, conventional αβ T cells, CD4+ regulatory T cells, natural killer T cells, γδ T cells, macrophages, and dendritic cells. [ABSTRACT FROM AUTHOR]

Summary: The control of the differentiation pathways followed by responding CD8+ T cells to produce protective memory cells has been intensely studied. Recent developments have identified heterogeneity at the effector cytotoxic T-lymphocyte level within which a bona fide memory cell precursor has emerged. The challenge now is to identify the cellular and molecular factors that control this developmental pathway. This review considers aspects of the regulation of the induction of effectors, the transition of effectors to memory cells, and the dynamics of the memory population. [ABSTRACT FROM AUTHOR]

Summary: CD8+ T cells (also called cytotoxic T lymphocytes) play a major role in protective immunity against many infectious pathogens and can eradicate malignant cells. The path from naive precursor to effector and memory CD8+ T-cell development begins with interactions between matured antigen-bearing dendritic cells (DCs) and antigen-specific naive T-cell clonal precursors. By integrating differences in antigenic, costimulatory, and inflammatory signals, a developmental program is established that governs many key parameters associated with the ensuing response, including the extent and magnitude of clonal expansion, the functional capacities of the effector cells, and the size of the memory pool that survives after the contraction phase. In this review, we discuss the multitude of signals that drive effector and memory CD8+ T-cell differentiation and how the differences in the nature of these signals contribute to the diversity of CD8+ T-cell responses. [ABSTRACT FROM AUTHOR]

Summary: The mammalian target of rapamycin (mTOR) is an intracellular kinase that regulates cell growth and metabolism. Its specific inhibitor rapamycin is currently used in transplant recipients as an immunosuppressive drug to prevent allograft rejection. Studies have shown complex and diverse mechanisms for the immunosuppressive effects of rapamycin. The drug has been reported to inhibit T-cell proliferation, induce anergy, modulate T-cell trafficking, promote regulatory T cells, and also prevent maturation of dendritic cells as well as production of type I interferon. However, several other studies have paradoxically demonstrated immunostimulatory effects of rapamycin by improving antigen presentation and regulating cytokine production from macrophages and myeloid dendritic cells. Recently, it has been shown that rapamycin also exhibits immunostimulatory effects on memory CD8+ T-cell differentiation. The drug improved both quantity and quality of memory CD8+ T cells induced by viral infection and vaccination, showing that mTOR is a major regulator of memory CD8+ T-cell differentiation. These discoveries have implications for the development of novel vaccine regimens. Here, we review the role of mTOR in memory CD8+ T-cell differentiation and compare the effect of rapamycin among CD8+ T cells, CD4+ T cells, and dendritic cells. Also, we discuss potential application of these findings in a clinical setting. [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]

Summary: Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) use cytotoxic granules containing perforin and granzymes to lyse infected or malignant host cells, thereby providing immunity to intracellular microbes and tumors. Perforin is essential for cytotoxic granule-mediated killing. Perforin expression is regulated transcriptionally and correlates tightly with the development of cells that can exhibit cytotoxic activity. Although a number of genes transcribed by T cells and NK cells have been studied, the cell-specificity of perforin gene expression makes it an ideal model system in which to clarify the transcriptional mechanisms that guide the development and activation of cytotoxic lymphocytes. In this review, we discuss what is known about perforin expression and its regulation, then elaborate on recent studies that utilized chromosome transfer and bacterial artificial chromosome transgenics to define a comprehensive set of cis-regulatory regions that control transcription of the human PRF1 gene in a near-physiologic context. In addition, we compare the human and murine Prf1 loci and discuss how transcription factors known to be important for driving CTL differentiation might also directly regulate the cis-acting domains that control Prf1. Our review emphasizes how studies of PRF1/Prf1 gene transcription can illuminate not only the mechanisms of cytotoxic lymphocyte differentiation but also some basic principles of transcriptional regulation. [ABSTRACT FROM AUTHOR]

Tumor immunosurveillance relies on cognate immune effectors [lymphocytes and interferon-γ (IFN-γ)] and innate immunity [natural killer (NK) cells, natural killer group 2, member D (NKG2D) ligands, perforin/granzyme, and tumor necrosis factor-related apoptosis-inducing ligand]. In parallel, tumor cells promote the expansion of CD4+CD25+ regulatory T cells (Tregs) that counteract T-cell-based anti-tumor immunity. Moreover, accumulating evidence points to a critical role for Tregs in dampening NK cell immune responses. This review summarizes the findings showing that Tregs suppress NK cell effector functions in vitro and in vivo, i.e. homeostatic proliferation, cytotoxicity, and interleukin-12-mediated IFN-γ production. The molecular mechanism involve selective expression of membrane-bound transforming growth factor-β on Tregs, which downregulate NKG2D expression on NK cells in vitro and in vivo. The regulatory events dictating NK cell suppression by Tregs have been studied and are discussed. The pathological relevance of the Treg–NK cell interaction has been brought up in tumor models and in patients with cancer. Consequently, inhibition of Tregs through pharmacological interventions should be considered during NK-cell-based immunotherapy of cancer. [ABSTRACT FROM AUTHOR]

Summary: Recent studies suggest that lineage commitment steps, which occur during T-cell differentiation, follow principles in common with fate specification in simple invertebrates. Here we review T-cell development from the perspective of developmental biology. We present models for αβ vs γδ and CD4 vs CD8 lineage commitment that are consistent with previously published and newly presented experiments. [ABSTRACT FROM AUTHOR]

Human and mouse studies performed over the last decade have established that follicular helper T (Tfh) cells are a CD4+ helper subset specialized in the provision of help to B cells. Tfh differentiation is driven by expression of the transcriptional repressor B-cell lymphoma-6 (Bcl-6), which turns on a program that guides T cells close to B-cell areas where Tfh cells first provide help to B cells. Sustained Bcl-6 expression promotes the entry of Tfh cells into follicles and modulates their cytokine expression profile so they can support and select germinal center B cells that have acquired affinity-enhancing mutations in their immunoglobulin genes. Forkhead box 3 protein (Foxp3)+ regulatory T cells and invariant natural killer T (NKT) cells can also co-opt the Bcl-6-dependent follicular differentiation pathway to migrate into B-cell follicles and regulate antibody responses. The resulting NKT follicular helper cells drive a distinctive type of T-dependent B-cell response to lipid-containing antigens, whereas FoxP3+ follicular regulatory (Tfr) cells exert a suppressive function on germinal centers. Elucidating how Tfr cells are functionally and numerically regulated and the factors that control the balance between Tfh and Tfr cells is likely to be critical for improved understanding of the pathogenesis and progression of autoimmunity and lymphomas of germinal center origin, and generation of effective vaccines. [ABSTRACT FROM AUTHOR]

T-cell help to B cells is a fundamental aspect of adaptive immunity and the generation of B-cell memory (memory B cells and plasma cells). Follicular helper CD4+ T (Tfh) cells are the specialized providers of B-cell help, and Tfh cells depend on Bcl6 for their differentiation. This review discusses Tfh cell functions, transcription factors, and induction signals, with particular focus on the richness of the underlying biology and assessing the simplicity or complexity of each of these processes. [ABSTRACT FROM AUTHOR]