2006 — 2010 |
Goldrath, Ananda W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
T Cell Maintenance: Molecular Mediators of the Tcr-Derived Survival Signal @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): Mature T cells persist within the body for indefinite periods of time, providing protection from a vast array of pathogens. A fraction of naive T cells survive for decades and some memory T cells survive for a lifetime without re-exposure to antigen. It is not known how the lifespan of T cells is regulated at the individual, cellular level or at the population level. Identification of the cellular and molecular interactions regulating the protracted persistence of both naive and memory T cells is essential to understanding T cell homeostasis and immunological memory. The goals of the experiments outlined in this proposal are to identify the molecular mediators of T cell survival downstream of the T cell receptor in naive T cells and determine if memory T cells utilize those same factors. Preliminary data suggest that a survival pathway may exist downstream of TCR:MHC interactions in which TCR signaling modulates expression of Early growth response (Egr) transcription factors and inhibitory DNA binding (Id) proteins (repressers of E protein transcription factors). We will test the hypothesis that interactions between TCR and self-peptide/MHC molecules and/or ligand independent TCR signaling support a gene-expression profile conducive to T cell survival. A new model system will be created to test if the activity of Egr transcription factors support the homeostasis/survival of naive, effector and memory T cells. To this end, a mouse model expressing a T cell specific, dominant-interfering form of Egr in a tetracycline-regulatable fashion will allow the "turn-off of Egr-mediated transactivation at key stages of T cell maturation. The role of Id proteins in the homeostasis and survival of naive, effector and memory T cells will also be examined utilizing Id2-deficient mice. As the expression of Egr and Id molecules is maintained by TCR-derived signals in naive T cells, the role of TCR surface expression and Egr/ld activity in the homeostasis and/or survival of memory T cells will also be examined. Furthermore, the possibility that TCR, interleukin-7-receptor and/or interleukin-15-receptor-mediated signals may synergize in maintaining the memory population will be explored. These studies will improve our understanding of how the immune system recovers following treatment- or illness-induced lymphopenia (such as chemotherapy or HIV infection) and aid in the design of vaccines that provide long-lasting protection from infection. Moreover, by expanding our understanding of how lymphocyte populations are regulated, it will be possible to gain insight into how normal survival signals are co-opted and how homeostatic set points are overcome by cancer cells providing possible targets for therapeutic intervention. [unreadable] [unreadable] [unreadable]
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1 |
2007 — 2008 |
Goldrath, Ananda W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
T Cell Maintenance: Molecular Mediators of the Tcr-Derived Survival Signal @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): Mature T cells persist within the body for indefinite periods of time, providing protection from a vast array of pathogens. A fraction of naive T cells survive for decades and some memory T cells survive for a lifetime without re-exposure to antigen. It is not known how the lifespan of T cells is regulated at the individual, cellular level or at the population level. Identification of the cellular and molecular interactions regulating the protracted persistence of both naive and memory T cells is essential to understanding T cell homeostasis and immunological memory. The goals of the experiments outlined in this proposal are to identify the molecular mediators of T cell survival downstream of the T cell receptor in naive T cells and determine if memory T cells utilize those same factors. Preliminary data suggest that a survival pathway may exist downstream of TCR:MHC interactions in which TCR signaling modulates expression of Early growth response (Egr) transcription factors and inhibitory DNA binding (Id) proteins (repressers of E protein transcription factors). We will test the hypothesis that interactions between TCR and self-peptide/MHC molecules and/or ligand independent TCR signaling support a gene-expression profile conducive to T cell survival. A new model system will be created to test if the activity of Egr transcription factors support the homeostasis/survival of naive, effector and memory T cells. To this end, a mouse model expressing a T cell specific, dominant-interfering form of Egr in a tetracycline-regulatable fashion will allow the "turn-off of Egr-mediated transactivation at key stages of T cell maturation. The role of Id proteins in the homeostasis and survival of naive, effector and memory T cells will also be examined utilizing Id2-deficient mice. As the expression of Egr and Id molecules is maintained by TCR-derived signals in naive T cells, the role of TCR surface expression and Egr/ld activity in the homeostasis and/or survival of memory T cells will also be examined. Furthermore, the possibility that TCR, interleukin-7-receptor and/or interleukin-15-receptor-mediated signals may synergize in maintaining the memory population will be explored. These studies will improve our understanding of how the immune system recovers following treatment- or illness-induced lymphopenia (such as chemotherapy or HIV infection) and aid in the design of vaccines that provide long-lasting protection from infection. Moreover, by expanding our understanding of how lymphocyte populations are regulated, it will be possible to gain insight into how normal survival signals are co-opted and how homeostatic set points are overcome by cancer cells providing possible targets for therapeutic intervention. [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2012 |
Goldrath, Ananda W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cd8 Immunity to Intracellular Infection: Control by E-Box Transcription Factors @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): The CD8+ T cell response to intracellular pathogens such as bacteria, viruses and protozoan parasites is an essential component of host resistance. This proposal utilizes experimental infectious disease models of bacteria, Listeria monocytongenes, and Vaccinia virus to address questions about the host CD8+ T cell immune response against potential microbial agents of bioterrorism. [unreadable] [unreadable] We have discovered that E protein transcription factors and their inhibitor, Id2, regulate the CD8+ T cell response to intracellular pathogens, which is a novel function for these proteins. It is our goal to understand at a molecular level how this family of transcriptional regulators influences the activation, proliferation, differentiation and survival of CD8+ T cells as they transition from naove to effector to memory cells. While the E proteins are known to regulate many key developmental check-points, lineage commitment, proliferation and survival during hematopoiesis and lymphocyte development, the function of these important proteins is unexplored in the mature T cell. [unreadable] [unreadable] We hypothesize that the activation of CD8+ T cells and subsequent generation of memory cells during the immune response involves the regulation of E protein- transcriptional targets. To gain insight into the specific E protein-transcription factors that regulate gene expression, the genes which are regulated by their activity during the CD8+ T cell response and how the inhibition of their activity regulates memory T cell formation, we propose to: Aim 1: Determine which E proteins regulate the in vivo CD8+ T cell response. We will examine the immune response by E2A, E2-2 and HEB-deficient T cells and the DNA-binding activity of each of these proteins during infection with Listeria monocytogenes and Vaccinia virus. Aim 2: Identify the molecular pathways controlled by E protein-transcription factors during the in vivo CD8+ T cell immune response to infection. Aim 3: Create an Id2-reporter mouse line to define the Id2 expression pattern during the immune response and determine if Id2 expressing effector T cells are the precursors to memory T cells. [unreadable] [unreadable] [unreadable]
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1 |
2011 — 2015 |
Goldrath, Ananda W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
T Cell Maintenance: Molecular Mediators of T Cell Differentiation and Survival @ University of California San Diego
DESCRIPTION (provided by applicant): Understanding how the survival, differentiation and formation of effector and memory T cells are coordinated during the response to infection is of significant importance to human health. Our studies aim to define the molecular pathways underlying the generation and function of human memory T cells, which provide protective immunity from recurring infections. As the molecular pathways that mediate the induction of long-lived memory T cells during the immune response are deciphered, the strategic design of therapeutic and protective vaccines will be improved.)
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1 |
2012 — 2015 |
Goldrath, Ananda W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Metabolic Regulation of T Cell Immunity @ University of California San Diego
DESCRIPTION (provided by applicant): To generate a robust and effective immune response, T cells must integrate pathogen-derived and micro- environmental signals; these include availability of nutrients and oxygen. Together these signals regulate the metabolic changes necessary for the dramatic expansion of effector T cells armed to eliminate pathogens. We have found that a specific metabolic response pathway controls T cell immunity, and will identify the signaling and physiological parameters that link the metabolic activity of T cells during their response to pathogen with their differentiation and function. )
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1 |
2013 — 2017 |
Goldrath, Ananda W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Cd8 Immunity to Intracellular Infections @ University of California San Diego
DESCRIPTION (provided by applicant): The CD8+ T cel response to intracellular pathogens such as bacteria, viruses, and protozoan parasites is a key element of host resistance to infections. To generate a robust and effective immune response, CD8+ T cells must integrate pathogen-derived and micro-environmental signals, including availability of nutrients and oxygen. Together these signals regulate the changes necessary for the dramatic expansion of effector T cells armed to eliminate pathogens and for the generation of immunological memory. In these studies, we will work to understand how the highly conserved HIF pathway, which plays a central role in regulating metabolism and the response to cellular stress caused by oxygen deficiency/hypoxia, functions in CD8+ T cells. We find that the response to acute and chronic infections are differentially impacted by HIF activity, suggesting that this pathway, which has not been studied in the context of CD8+ T cell responses, controls multiple aspects of the attenuation of effector and memory T cell function, differentiation, and immunopathology. Results from these studies will provide novel insights into the CD8+ T cell immunity, a topic of significance in the development of treatment strategies and vaccines for chronic infections, emerging infectious agents, and microorganisms relevant to biodefense. Furthermore, we will study the clinical relevance of pharmacologic stabilization of HIF, a molecule targeted in numerous disease contexts, to CD8+ T cell function.
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1 |
2014 — 2018 |
Goldrath, Ananda W |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Tf Regulation of Cd8 and Cd4 T Cell Memory in Both Systemic and Dermal Infection @ La Jolla Inst For Allergy & Immunolgy
The CD8+ T cell response is a key element of host resistance to viral infections. To generate a robust and effective immune response, CD8+ T cells must integrate pathogen-derived and micro-environmental signals, including availability of nutrients and oxygen. Together these signals regulate the changes necessary for the dramatic expansion of effector T cells armed to eliminate pathogens and for the generation of immunological memory. In these studies, we will work to understand the transcriptional control of CD8+ immunity using novel strategies that use function-based screening approaches to identify molecules that control formation of protective immunity. In particular, we will explore how T cell function and memory formation is impacted at the transcriptional level within the context of dermal infection. Results from these studies will provide novel insights into T cell immunity, a topic of significance in the development of treatment strategies and vaccines for chronic infections, emerging infectious agents, and microorganisms relevant to biodefense.
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0.903 |
2016 — 2020 |
Bier, Ethan Goldrath, Ananda W Hedrick, Stephen M [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mutagenic Chain Reaction-Facilitated Immunotherapy @ University of California San Diego
Project Summary/Abstract The objectives of this project are to reprogram primary T cells as a means of eliminating cancer cells?a major goal of biomedical research as mandated by the National Institutes of Health. Using new genetic tools applied in novel ways, we will overcome present limitations to cancer immunotherapy by produc- ing T cells that have been relieved of multiple inhibitory feedback mechanisms. However, the more ef- fective the T cell population in eliminating cancerous cells, the more likely they are to cause inflammato- ry immunopathology. Thus, an important requirement for this reprogramming is to provide a provision for their elimination. The means for producing such T cells relies on a recently developed autocatalytic gene conversion method based on the Crispr/Cas9 system and known as the mutagenic chain reaction (MCR). There are two primary advantages to our integrated system for reprogramming T-cells. First, our meth- od should be substantially more efficient in generating biallelic insertions that can render cells defective for multiple genes. Second, because MCR vectors integrate larger inserts into the genome with high effi- ciency and fidelity, we will be able to introduce a multifunctional cassette of genetic elements (e.g., sgR- NAs targeting multiple inhibitory pathways and an inducible suicide module). Combined, these two fea- tures will make it possible to reprogram effector T cells in a single round of ex vivo treatment reducing the number of cell divisions that take place in culture and minimizing the time from cell retrieval to rein- fusion of tumor-fighting T cells. The anti-tumor efficacy of reprogrammed T cells will be studied in models of solid and metastatic melanoma to identify the optimal combination of targeted inhibitory pathways. Initial experiments will take advantage of mouse models, with experiments progressing to the reprogramming of cultured human T cells. These techniques will enable a generation of novel therapies to treat cancer, but also chronic infectious diseases, autoimmunity, and allergic hypersensitivity diseases.
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1 |
2017 — 2021 |
Goldrath, Ananda W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
T Cell Maintece: Molecular Mediators of T Cell Differentiation and Survival @ University of California, San Diego
Summary: Despite extraordinary medical advances in the last century, infectious diseases remain the second leading cause of death worldwide, and disease-associated morbidity causes immeasurable harm. The development of new vaccines is, therefore, an imperative for improving global health. The ability of adaptive immune cells to respond more rigorously after a primary exposure, preventing pathology, and in essence ?remembering? the infection is the basis for vaccination. A heterogeneous population of long-lived memory T cells mediate protection from reinfection with previously encountered pathogens; keep chronic, opportunistic and latent pathogens at bay; and defend against tumor growth and metastases. Thus, understanding how memory lymphocytes are induced and sustained is of central importance in the rational design of new vaccines. Tissue- resident memory T cells provide sentinel protection at body surfaces such as the intestinal epithelium, and provide a first line of adaptive immune defense to reinfection. While we now know that tissue-resident T memory cells provide an essential component of immune memory, the transcriptional pathways regulating their formation, survival, and function, and how these relate to those that promote the formation of other memory populations are poorly understood. Improving our understanding of these topics will allow us to harness the immediate protective capacity of this vital memory T cell population in tissues where infections typically begin and modulate activity in the context of immunopathology. To this end, we present a preliminary in vivo functional screen that identifies numerous new regulators of CD8+ tissue-resident memory T cell differentiation. Based on these novel findings, we propose to: (1) Study how Runx3 and Blimp1 support the formation, homeostasis, and function of the CD8+ tissue-resident memory T cell population. (2) Delineate the role of the bromodomain and extraterminal domain (BET) epigenetic ?reader? of histone acetylation, Brd4, in regulating gene expression during memory T cell differentiation. (3) Define the transcriptional network that regulates CD8+ tissue-resident memory T cell formation. By using single-cell sequencing and comparison of open chromatin regions in CD8+ tissue-resident memory T cell populations to predict important transcriptional regulators, we will expand our in vivo screening strategy to identify regulators of CD8+ tissue-resident memory cells. We will leverage the results to enhance tissue-resident memory activity in the context of tumor growth and viral infection. By discovering the transcriptional program and molecular regulators promoting differentiation, survival, and function of tissue- resident memory T cells, we will identify novel targets that can be exploited in the strategic design of therapeutic and protective vaccines, the development of which are of crucial importance to human health.
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1 |
2018 — 2021 |
Goldrath, Ananda W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Administrative Core @ University of California, San Diego
SUMMARY-ADMINISTRATIVE CORE: This Program Project encompasses three Scientific Projects and two Scientific Cores, bringing together personnel with diverse backgrounds, motivations, and expertise. We aim to rapidly uncover the developmental pathway and transcriptional programming of tissue-resident memory CD8+ T cells in acute and chronic infection. We have identified the following two critical challenges for success of this multi-team effort: (1) building and maintaining a common vision among all team members, and (2) establishing smooth and efficient sharing of data, reagents, and technology, to best coordinate experimental strategy between Projects. The Administrative Core will address these needs and contribute to the goals of the Program Project by (1) acting as a communication hub at all levels and for all involved personnel, while (2) providing general administrative support and fiscal oversight. The Administrative Core thus plays a central role in the Program Project's efforts, and in the following, we lay out the specifics of its activities. !
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1 |
2018 — 2021 |
Goldrath, Ananda W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Molecular Determits of Tissue-Resident Memory T Cell Fate in Acute and Chronic Infection @ University of California, San Diego
OVERALL SUMMARY: Mortality from infectious diseases remains the second leading cause of death worldwide; a further toll on human health is exacted by disease-associated morbidity. The development of new vaccines is, therefore, an important priority for improving global health. Immunological memory is a cardinal feature of adaptive immunity and its induction is the underlying goal of vaccination. Long-lived memory T cells mediate protection from reinfection with previously encountered pathogens; keep chronic, opportunistic and latent pathogens at bay; and can serve as endogenous defenders against tumor growth and metastases. The memory T cell population is heterogeneous, typically categorized into central memory cells found in the blood and lymphoid tissues, or effector memory cells predominantly located in the blood and non-lymphoid tissues. The recent recognition of a third subset of memory lymphocytes, termed tissue-resident memory cells (Trm), that reside strictly within tissues and do not recirculate requires a revision of our understanding of memory T cell differentiation. Tissue- resident T cells provide essential sentinel protection at body surfaces such as the intestinal epithelium, and, are now clearly understood to be among the key `first responders' in many infection settings. Although we now know that resident-memory cells are an essential component of immune memory, little is known about the transcriptional pathways regulating their formation, survival and function. Improving our understanding of these topics will allow us to harness the immediate protective capacity of this vital memory T cell population and modulate activity in the context of immunopathology. To this end, we propose three synergistic projects that all leverage novel single-cell, genomic and computational analyses provided by two Cores to: 1) Define the unanticipated roles of key transcription factors in Trm formation and identify novel molecular determinants of Trm differentiation and homeostasis; 2) Identify early molecular regulators of Trm cell fate specification within different tissues in the context of acute and chronic infections using single-cell analyses of gene expression and computational approaches; 3) Define exhausted Trm during chronic viral infection and identify core regulators that determine their accumulation and hypo-functional state. Understanding the generation and homeostasis of tissue-resident memory cells will allow the exploitation of the immediate protective capacity of this vital memory population and provide strategies to modulate this activity in the context of immunopathology. We have assembled a team of five laboratories, which together possess the tools and expertise to resolve the transcriptional network driving memory T cell formation and exploit this knowledge to realize advances in regulating immunity in tissues. !
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1 |
2018 — 2021 |
Goldrath, Ananda W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Project 1 - Goldrath @ University of California, San Diego
SUMMARY-PROJECT 1-GOLDRATH: Long-lived memory cells provide protection from reinfection and can serve as endogenous defenders against tumor growth and metastases. Tissue-resident memory T cells provide essential sentinel protection at body surfaces such as the intestinal epithelium, and are now clearly understood to be among the key `first responders' in many infection settings. Although we know that resident-memory cells are an essential component of immune memory, little is known about the transcriptional pathways regulating their formation, survival and function. Improving our understanding of these topics will allow us to harness the immediate protective capacity of this vital memory T cell population and modulate their activity in the context of immunopathology, which is the overarching goal of the Program Project. Benefiting from the combined expertise in cutting-edge epigenetic and genomic analyses, CD8+ T cell biology, and chronic infection of the Program Project and Core Leaders, Project 1 will define the relationship of transcriptional programs driving unique memory states with a focus on resident versus circulating memory populations. The heterogeneity, gene-expression programs, functional activity and regulatory elements involved in resident- memory cell development will be studied to generate an integrated understanding of how transcriptional regulators such as Blimp1, Bcl6, T-bet, and E/Id proteins drive divergent differentiation programs in memory cell precursors to promote differentiation of distinct memory fates. To this end, specifically, we will: (1) Define the relationship of transcriptional programs driving unique memory states to understand how resident-memory T cell differentiation diverges from circulating memory T cell populations. Single-cell analysis of gene expression will be paired with high-throughput functional screening to assess the hybrid transcriptional network regulating the formation and homeostasis of Trm populations. (2) Decipher the contradictory dependence of Trm on the antagonistic transcriptional repressors, Blimp1 and Bcl6 in Trm differentiation and homeostasis. (3) Resolve the role of E protein transcription factors and their regulators in the transcriptional network governing the development, function and homeostasis of tissue-resident memory T cells in acute and chronic infectious settings. Our studies identifying key molecular determinants and transcriptional programs that control resident- memory T cell fate specification are critical to inform the rational design of the next generation of vaccines that will specifically aim to invoke tissue-resident memory cell-mediated protection from infectious diseases and malignancy. !
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1 |
2018 — 2021 |
Goldrath, Ananda W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of T Cell Immunity to Viral Infection @ University of California, San Diego
SUMMARY: Naive T cells have the potential to differentiate into effector cells with a range of functions that aid in clearing pathogens as well as long-lived memory cells that provide protection from reinfection. CD4+ effector or T helper cells are defined by the cytokines they produce, which mediate the activity of innate, B cell, and CD8+ T cell immunity. The presence of numerous CD4+ T helper subsets has complicated the ability to define the relationship between effector and memory-precursor populations and identify the molecular mediators required to support the formation of CD4+ protective immunity. As CD4+ T cell help is required to sustain CD8+ T cell memory in many contexts, to support high-affinity memory B cell responses, and to direct activity of innate cells, we will seek to define the CD4+ memory T cell population(s) and their precursor(s) as well as the transcriptional networks driving differentiation and homeostasis of this vital component of immune memory. Further, our studies will explore the distinct differentiation requirements for CD4+ memory T cell populations that reside in non-lymphoid tissues and circulating memory populations. Tissue-resident memory cells are of particular interest in the context of vaccination as they provide essential sentinel protection at barrier surfaces, and, are now clearly understood to be among the `first responders' in many infection settings. Using single-cell analyses of protein and gene expression, genomic and computational approaches, and in vivo functional screens as well as traditional adoptive transfers of cells that can report expression of or are mutant for candidate regulators, we will comprehensively study CD4+ memory T cell formation in response to viral infection. These studies will provide the basis to exploit the protective capacity of this vital memory T cell population and modulate activity in the context of immunopathology. Direct targeting of specific transcriptional regulators during vaccination holds promise as a novel strategy in the control of induced immunity. !
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1 |
2020 |
Goldrath, Ananda W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Regulation of Memory T Cell Differentiation and Long-Term Maintece @ La Jolla Institute For Immunology
PROJECT SUMMARY / ABSTRACT Project 3 (Goldrath) In response to infection, many cellular factors cooperate to direct T cells through their expansion and differentiation to effector cells that mediate pathogen clearance and memory cells that persist to provide long- lived host protection from reinfection. Harnessing the functionality and longevity of memory T cells is the basis for some vaccines and has become an attractive approach in cancer immunotherapy. However, the memory T cell pool is heterogeneous, and it is currently unclear which subsets confer optimal protection during malignancy or infection and how these subsets are transcriptionally programmed. We propose to define the transcriptional and chromatin regulatory factors of memory T cell subset differentiation following infection and identify those that promote accumulation and function of anti-tumor cytotoxic lymphocytes. Further, we will explore the relationship between changes in chromatin configuration and memory T cell-specific transcriptional programs. We propose highly collaborative Aims which leverage the expertise, infrastructure and technologies unique to the Crotty- Pipkin-Goldrath laboratories and Cores. Specifically, we will: (1) Resolve the functional heterogeneity and transcriptional programming of circulating CD8 memory T cell populations. (2) Define the transcriptional and epigenetic programming of stem-like memory, effector, and tissue-resident CD8 T cell subsets in tumors. (3) Resolve the roles of Blimp1 and Bcl6 in programming distinct CD4 memory T cell populations. (4) Dissect the mechanism(s) by which the chromatin regulatory factor CTCF instructs memory T cell differentiation. By developing an understanding of the factors that control differentiation and function of memory T cell subsets, it may be possible to induce or regulate their activity in the context of infection, malignancy, and immunopathology.
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0.904 |