Transcriptional Regulation of Memory T Cell Differentiation PDF Download

Author: Myoungjoo Kim
Publisher:
ISBN:
Category :
Languages : en
Pages : 238

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Memory T cells protect hosts from pathogen reinfection, but how these cells emerge from a pool of antigen-experienced T cells is unclear. Here we show that mice lacking the transcription factor Foxol in activated CD8 + T cells had defective secondary, but not primary, responses to Listeria monocytogenes infection. Compared to short-lived effector T cells, memory precursor T cells expressed higher amounts of Foxo1, which promoted their generation and maintenance. Chromatin immunoprecipitation sequencing experiments revealed the transcription factor Tcf7 and the chemokine receptor Ccr7 as Foxo1-bound target genes, which have critical functions in central memory T cell differentiation and trafficking. These findings demonstrate that Foxol is selectively incorporated into the genetic program that regulates memory CD8 + T cell responses to infection.

Author: R. Ahmed
Publisher: Wiley-Blackwell
ISBN:
Category : Medical
Languages : en
Pages : 754

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Persistent Viral Infections Edited by Rafi Ahmed Emory Vaccine Center, Atlanta, USA and Irvin S. Y. Chen UCLA School of Medicine, Los Angeles, USA During the past decade much of our attention has focused on diseases associated with viral persistence. Major breakthroughs in immunology, and the advent of molecular approaches to study pathogenesis have increased our understanding of the complex virus-host interactions that occur during viral persistence. Persistent Viral Infections focuses on: * The pathogenesis and immunology of chronic infections * Animal models that provide, or have the potential to provide, major insights This volume will be essential reading for virologists, immunologists, oncologists and neurologists.

Author: Jonathan Soboloff
Publisher: CRC Press
ISBN: 149870509X
Category : Medical
Languages : en
Pages : 258

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Book Description
T cells play a vital role mediating adaptive immunity, a specific acquired resistance to an infectious agent produced by the introduction of an antigen. There are a variety of T cell types with different functions. They are called T cells, because they are derived from the thymus gland. This volume discusses how T cells are regulated through the operation of signaling mechanisms. Topics covered include positive and negative selection, early events in T cell receptor engagement, and various T cell subsets.

Author: John Adam Best
Publisher:
ISBN: 9781267834683
Category :
Languages : en
Pages : 85

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CD8 T cells posses the dual function of specifically targeting and killing host cells harboring intracellular pathogens, while at the same time maintaining the ability to "remember" the invader and protect against subsequent infection. The cellular decision to terminally differentiate as an effector cell or to maintain the ability to renew and persist as a memory call are guided in large part by the complex interaction of extracellular signaling leading to differential expression of various transcription factors. These factors co-operate to direct CD8 T cells through their dramatic expansion and differentiation to effector and memory cells. Utilizing the unparalleled breadth of data and metadata from the Immunological Genome Project and conditional deletion of CD8+ associated transcription factors, we analyzed antigen-specific CD8+ T cells throughout differentiation to establish dynamic gene-expression signatures and identify putative transcriptional regulators throughout the response to infection. Notably, these gene-expression signatures can predict memory-precursor potential of effector CD8+ T cells. While distinct inflammatory milieu and T cell precursor frequencies are known to shift differentiation of CD8+ effector and memory populations, we found that core transcriptional signatures were nearly identically regulated, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Ultimately, long-lived memory CD8+ T cells stably expressed of a small subset of genes shared by NKT and a subset of [gamma][delta] T cells, consistent with common effector capacities. Meta-data analyses led to the discovery of Zeb2, a transcription repressor, which we subsequently showed is necessary for the formation of the subset of terminally differentiated effector CD8+ T cells. These results provide a framework for the future study of T cell differentiation during infection and provide insight into transcriptional regulation influencing immunological memory formation and vaccine efficacy.

Author: Varun N. Kapoor
Publisher:
ISBN:
Category :
Languages : en
Pages : 438

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Author: Keiko Ozato
Publisher: Frontiers Media SA
ISBN: 2889637239
Category :
Languages : en
Pages : 149

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Transcription depends on an ordered sequence of events, starting with (i) setting of the enhancer and chromatin environment, (ii) assembly of DNA binding and general transcription factors, (iii) initiation, elongation, processing of mRNA and termination, followed by (iv) creation of epigenetic marks and memory formation. Highlighting the importance of these activities, more than 10% total genes are dedicated to regulating transcriptional mechanisms. This area of research is highly active and new insights are continuously being added to our knowledge. Cells of the immune system have unique features of gene regulation to support diverse tasks required for innate and adaptive immunity. Innate immunity involves the recognition of external infectious and noxious agents as well as internal cancer cell components, and the elimination of these agents by non-specific mechanisms. Adaptive immunity involves gene rearrangement to achieve highly specific T and B cell responses, imparting the capability of self and non-self discrimination. This requires transcription and epigenetic regulation. Adaptive immunity also employs epigenetic memory, enabling recapitulation of prior transcription. Recent advances in nuclear architecture, chromatin structure, and transcriptional regulation have provided new insights into immune responses. The increased understanding of these molecular mechanisms is now affording opportunities to improve therapeutic strategies for various diseases.

Author: Rémy Bosselut
Publisher: Humana
ISBN: 9781493928088
Category : Medical
Languages : en
Pages : 0

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​This volume provides simple and accessible experiment protocols to explore thymus biology. T-Cell Development: Methods and Protocols is divided into three parts presenting short reviews on T cell development, analysis strategies, protocols for cell preparation, flow cytometry analyses, and multiple aspects of thymocyte biology. As a volume in the highly successful Methods in Molecular Biology series, chapters contain introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and tips on troubleshooting and avoiding known pitfalls. Concise and easy-to-use, T-Cell Development: Methods and Protocols aims to ensure successful results in the further study of this vital field.

Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 0

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Although in CD8 T cells, NF-kappa-B family members, are known to play a role in T cell activation, proliferation and activation, effector function, and differentiation, it remains unclear whether the dependence on I-kappa-B-alpha for export of NF-kappa-B proteins plays a role in, effector and/or memory CD8 T cell differentiation, and maintenance of memory CD8 T cells during an acute infection. Dr. Miyamoto has developed the NfkbiaNES/NES mice, in which the nuclear export sequence of I-kappa-B-alpha is mutated, and thus NF-kappa-B export from the cell nucleus to the cytoplasm does not occur. Using these mice, in chapter five, I investigated the physiological significance of I-kappa-B-alpha nuclear export in CD8 T cell differentiation during an acute LCMV infection. Strikingly, we found that the NES mutation of I-kappa-B-alpha greatly diminishes CD8 T cell activation, differentiation, and IFN-gamma production among virus-specific effector CD8 T cells. We also found that it regulates CD8 T cell memory differentiation by the reduction of key transcription factors such as FoxO1 and TCF-1. Together, these findings have provided fundamental insights into the role of I-kappa-B-alpha nuclear export of NF-kappa-B and its regulation of the homeostasis of CD8 T cell memory to intracellular pathogens. CD4 T cells, otherwise known as "T helper cells" are mainly recognized for their ability to help B cell and CD8 T cell responses. Current research has elucidated many different CD4 T cell lineages, their memory differentiation, and additional roles for these CD4 T cells in immunity to viruses. Unlike the field of memory CD8 T cells, the field of memory CD4 T cells must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. To date there are at least seven distinct CD4 T cell effector lineages: TH1, TH2, TH17, TFH TREG, TH22, and TH9. Parallel to the effector CD8 T cell population, effector CD4 T cell lineage commitment is established early in response to infection, which is followed by their differentiation into a heterogeneous population of effector CD4 T cells that can then acquire unique characteristics that endow them with the ability to become a stable pool of memory CD4 T cells. Their cell fate is influenced by signaling during priming as well as by signals acquired during the effector stage and clearance of the infection. Thus, the nature and combination of the cytokine signaling in the local environmental milieu of activated CD4 T cells influences their proliferative potential, effector differentiation, and memory capacities. Further, the balance of these signals, otherwise known as "polarizing conditions", helps drive CD4 T cell lineage commitment by inducing lineage-defining cytokines and their respective transcription factors. Hence, the mechanisms that regulate the number and quality of memory CD4 T cells is very poorly understood. In chapter six, I elucidate a novel role of I-kappa-B-alpha nuclear export of NF-kappa-B in CD4 T cell differentiation during an acute LCMV infection. In this study, we report that nuclear export of I-kappa-B-alpha plays an integral role in the differentiation of TH1 and TFH CD4 T cell memory subsets by regulating the balance of key transcription factors T-bet, Bcl-6 and Blimp-1. We also find that the NES mutation in I-kappa-B-alpha dysregulates the antigen-induced production of IFN-gamma by virus-specific CD4 T cell. Hence, we propose that nuclear export of I-kappa-B-alpha is a key regulator that steers TH1 and TFH CD4 T cell memory differentiation. These findings have provided fundamental insights into the mechanisms that regulate CD4 T cell differentiation and viral clearance. In conclusion, my studies have elucidated and advanced our understanding for the molecular requirements of both FoxO1 and I-kappa-B-alpha in the differentiation and functionality of T cells during an acute viral infection. These findings suggest that the modulation of FoxO1 and I-kappa-B-alpha is a promising strategy to enhance T cell responses to vaccinations or acute viral infections.

Author: Dragana Jankovic
Publisher: Frontiers Media SA
ISBN: 2889195651
Category : Immunologic diseases
Languages : en
Pages : 113

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Book Description
CD4+ T lymphocytes play an essential role in host defense against bacterial, parasitic and viral infections. During infection, under the influence of intrinsic signals received through peptide-MHC/TCR interactions and extrinsic signals provided by pathogen-conditioned dendritic and other accessory cells, CD4+ T cells proliferate and differentiate into specialized T helper (Th) effectors, which produce distinct sets of cytokines tailored to combat a specific class of microbes. The concept of CD4+ T cell multi-functionality was developed after the seminal discovery of Th1 and Th2 cells nearly 30 years ago. Although the Th1/Th2 paradigm has successfully withstood the test of time, in the past decade additional Th subsets (Th17, Tfh, Th22, Th9) have been identified. Similarly, single cell analyses of cytokines and master transcriptional factors have revealed that, at the population level, CD4+ T cell responses are far more heterogeneous than initially anticipated. While some of the checkpoints in Th cell specification have been identified, recent studies of transcriptional and epigenetic regulation have uncovered a significant flexibility during the course CD4+ T lymphocyte polarization. In addition, Th cells expressing cytokines with counteracting functions, as a measure of self-regulation, display yet another level of diversity. Understanding the mechanisms that control the balance between stability vs. plasticity of Th effectors both at the time of initiation of immune response and during development of CD4 T cell memory is critical for the rational design of better vaccines and new immunotherapeutic strategies. This research topic will cover current views on Th cell development, with a focus on the mechanisms that govern differentiation, function and regulation of effector Th cells in the context of microbial infections.

Author:
Publisher:
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Category :
Languages : en
Pages : 0

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T cells are a heterogeneous group of lymphocytes that are derived from the bone marrow and mature in the thymus before being disseminated to secondary lymphoid organs such as the spleen and lymph nodes. They are critical for anti-microbial defense via the promotion of appropriate antigen-specific primary adaptive responses against immunologic threats, the generation of immunologic memory, and the suppression of inappropriate immune responses. Antigen-specific memory responses are the hallmark of the adaptive immune system, and they are significantly more rapid and potent than primary antigen-specific responses. As a result, appropriate memory T cell responses can provide potent and long-lived protection from disease, while a lack of T cell memory may lead to failure of immunity, and inappropriate memory may result in potentially life-threatening immune-mediated diseases. The development of appropriate primary and memory T cell responses is highly complex, and requires the careful integration of diverse cytokine and cell-cell signals, the installation of specific transcriptional programs during differentiation, and profound alterations in proliferative and functional capacity. The rational design of prophylactic interventions such as vaccines to prevent infectious diseases, and the identification of therapeutic targets for the treatment of immune-mediated diseases depend upon a detailed understanding of these molecular mechanisms. In this thesis, I will discuss the cell-signaling and transcriptional bases of T cell effector and memory differentiation and homeostasis, and emphasize newly elucidated roles for the PI3K/Akt pathways, mTOR, and the FoxO transcription factors in the differentiation and regulation of CD8 T cells, and the roles of Bach2 in the differentiation of CD8 T cell memory and the development of CD4 Foxp3+ regulatory T cells. Naïve CD8 T cells respond to infection with viruses or intracellular bacteria, or the emergence of tumor cells by differentiating into cytotoxic T cells. These cytotoxic CD8 T cells are antigen-specific and their cytotoxicity is restricted to cells bearing the pathogen or tumor antigen. Antiviral CD8 T cell responses have been the best characterized. These responses are highly dynamic, and have been classically divided in to three distinct phases: expansion, contraction and memory. Only cells that successfully pass through all three phases may differentiate into bona fide memory cells capable of producing protective secondary responses. Thus, generation of appropriate memory depends upon a variety of molecular mechanisms occurring throughout the process, with critical checkpoints occurring during the initial activation of naïve cells, the successful transition between phases, and the orderly differentiation of T cell subsets within each phase. There is considerable evidence that the PI3K/Akt signaling pathway is activated via engagement of the TCR and co-stimulatory interactions, during the initial activation of naïve T cells by professional antigen-presenting cells. (APCs). Further evidence indicates that the Akt signaling pathway is concurrently modulated by changes in cellular metabolism and signaling by a variety of cytokines including IL-2, IL-7, IL-12 and IL-15. However, how these stimuli collectively activate the PI3K/Akt signaling pathway in vivo, and how this Akt signaling dictates the differentiation process of CD8 T cells during an acute viral infection are yet to be determined. Chapter Three reports the role of Akt signaling on the differentiation of CD8 T cells during an acute viral infection. Using genetic and pharmacological approaches, I have identified Akt as a signal integrator that accepts signals from TCR and cytokines like IL-2 and IL-12, and links downstream targets like mTOR and FoxO to distinct facets of CD8 T cell differentiation. Notably, sustained Akt signaling promotes the terminal differentiation of effector CD8 T cells, which results in the exaggerated contraction and the impaired formation and maintenance of memory CD8 T cells. These changes are induced at least in part through the hyper-activation of mTOR followed by the increased expression of T-bet. Moreover, inactivation of FoxO1 induced by constitutive Akt signaling downregulates IL-7R expression. Conversely, preventing excessive mTOR activation by in vivo rapamycin administration, and the forced expression of IL-7R significantly enhance the formation of memory CD8 T cells. Finally, in vivo inhibition of Akt signaling mitigates impaired generation of memory CD8 T cells. These findings imply that therapeutic modulation of Akt might be a strategy to enhance vaccine-induced immunity. One of several target genes affected by Akt signaling is the transcription factor Bach2. It has been originally identified as a B cell-specific transcription factor that maintains B cell identity and restrains differentiation of plasma cells. Notably, other groups and I have discovered that Bach2 is also expressed in the T cell compartment. Remarkably, CD8 T cells' progression towards terminal differentiation correlates with reduced expression of Bach2. Thus, it is likely that Bach2 regulates the homeostasis of naïve CD8 T cells and the differentiation of memory CD8 T cells, in which Bach2 mRNA is highly expressed. Therefore, in Chapter Four, I have investigated the effects of Bach2 on CD8 T cell differentiation during an acute viral infection. Similar to B cells, Bach2 deficiency promotes terminal differentiation of LCMV-specific CD8 T cells, and prevents efficient effector-to-memory transition in a cell-intrinsic manner. Additionally, in the absence of Bach2, tissue distribution of virus-specific CD8 T cells is affected. Remarkably, in the absence of Bach2, LCMV-specific memory T cells exhibits defective memory maintenance, which results in the gradual attrition of memory CD8 T cells. Together, my studies suggest that Bach2 exerts important effects on the formation and homeostasis of memory CD8 T cells by preventing terminal differentiation and by contributing efficient effector-to-memory transition and maintenance of virus-specific memory CD8 T cells. In contrast to a single effector subset of CD8 T cells, CD4 T cells (also known as helper T cells) can differentiate into various subsets of effector CD4 T cells, in which TH1, TH2, TH17 and follicular helper T cell (TFH) orchestrates immune responses to clear different types of pathogens such as virus, bacteria, fungi and parasites, while regulatory T cells (Treg) tone down activated immune responses in order to prevent immune-mediated pathology. A recent study has reported that the expression of Bach2 is dynamically regulated during Treg cell development. Moreover, I have found that T cells in Bach2-deficient mice show spontaneous activation. These findings have led us to investigate the function of Bach2 on Treg cell development and homeostasis. As described in Chapter Five, without Bach2, Treg cells exhibit attenuated foxp3 expression, diminished frequencies and numbers, enhanced activation and proliferation, and profound loss of competitive fitness in vivo. Importantly, Bach2 deficiency redirects the Treg differentiation program into a TH2 effector program by the increased expression of TH2-driving transcription factor, Gata3. Additionally, perturbations in the conversion of induced Treg cells in the periphery induced by Bach2 deficiency undermines optimal establishment of immune tolerance contributed by Treg cells. Strikingly, the abnormal homeostasis of Treg cells seems to be associated with systemic inflammation, especially a life-threatening eosinophilic crystalline pneumonia in Bach2-deficient mice. In summary, Bach2 enforces T cell quiescence, promotes the optimal development and homeostasis of Treg cells, and protects against immune-mediated diseases.