T Cell Memory to Viruses
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Principal Investigator: Rafi Ahmed Organization: EMORY UNIVERSITY Fiscal Year: 2024 Award: $620,693 Funding agency: National Institute of Allergy and Infectious Diseases Chronic viral infections are characterized by a state of T cell dysfunction that is associated with expression of the PD-1 (programmed cell death 1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8 T cell responses during chronic viral infection is required to improve immunotherapies that will increase T cell function and reduce viral load. We have recently identified a novel population of PD-1+ TCF-1+ virus specific CD8 T cells that act as stem cells to maintain T cell responses during chronic infection of mice with lymphocytic choriomeningitis virus (LCMV). The studies proposed in the application are focused on understanding how these virus specific stem-like CD8 T cells are generated and maintained during chronic infection and how this information can be used to develop rational approaches for optimizing PD-1 directed immunotherapy. In particular, we ask the following questions: 1) How do these cells maintain their quiescence and the stem-like state while living in a sea of antigen and getting TCR signals? 2) Are there any novel inhibitory pathways that are selectively expressed by the stem-like CD8 T cells to maintain their lifestyle during chronic infection? 3) How can we increase the number of these crucial stem-like CD8 T cells? 4) What are the most optimal PD-1 combination therapies for harnessing the full potential of the stem-like CD8 T cells? The following specific aims are proposed to address these questions: Specific Aim 1: Determine the role of inhibitory molecules selectively expressed by virus-specific stem-like CD8 T cells in regulating their quiescence and effector cell output. Specific Aim 2: Harnessing the potential of PD-1+ stem-like CD8 T cells for optimal immunotherapy in chronic viral infection. Terms: <Address><Antigen-Presenting Cells><Antigens><Autoimmune Status><Autoimmunity><Body Tissues><Bone-Derived Transforming Growth Factor><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chronic><Clinic><Collaborations><Combination immunotherapy><Combined Modality Therapy><Dysfunction><Effector Cell><Functional disorder><Goals><Health><Human><IL-7><IL-7 Gene><IL7><IL7 Protein><IL7 gene><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><Infection><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin-7><Interleukin-7 Gene><Intracellular Communication and Signaling><LCM Viruses><LCMV><Letters><Life Style><Lifestyle><Lymphatic Tissue><Lymphocytic choriomeningitis virus><Lymphoid><Lymphoid Tissue><Lymphopoietin-1><Malignant Neoplasms><Malignant Tumor><Mice><Mice Mammals><Milk Growth Factor><Modern Man><Multimodal Therapy><Multimodal Treatment><Murine><Mus><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Output><PD 1><PD-1><PD1><Pathway interactions><Physiopathology><Platelet Transforming Growth Factor><Play><Population><Progenitor Cells><Proliferating><Receptor Protein><Research Proposals><Research Resources><Resources><Role><Scientist><Sea><Signal Transduction><Signal Transduction Systems><Signaling><Site><Subcellular Process><T cell response><T memory cell><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Tissues><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><United States National Institutes of Health><Viral Burden><Viral Cancer><Viral Diseases><Viral Load><Viral Load result><Virus><Virus Diseases><Work><accessory cell><biological signal transduction><chronic infection><combination therapy><combinatorial immunotherapy><combined modality treatment><combined treatment><dual immunotherapy><exhaust><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><improved><insight><malignancy><memory T lymphocyte><multi-modal therapy><multi-modal treatment><neoplasm/cancer><non-human primate><nonhuman primate><novel><pathophysiology><pathway><persistent infection><progenitor cell differentiation><progenitor differentiation><programmed cell death 1><programmed cell death protein 1><programmed death 1><receptor><selective expression><selectively expressed><self-renew><self-renewal><sle2><social role><stem><stem and progenitor differentiation><stem cell differentiation><stem cells><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><viral infection><virus infection><virus-induced disease>