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Principal Investigator: Michael Gerner
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2019
Award: $524,320
Funding agency: National Institute of Allergy and Infectious Diseases
The innate and adaptive arms of the immune system are integrally linked, with dendritic cells (DCs), innate
antigen presenting cells, providing critical instructions to elicit the generation of adaptive T cell immunity. Using
a novel analytical imaging approach, we recently uncovered that different DC populations are asymmetrically
distributed in steady-state mouse lymph nodes, creating highly segregated zones composed of one or another
DC subset. Given that these DC populations have well-characterized differences in their abilities to elicit distinct
types of T cell responses, these findings raise the central hypothesis of this proposal, that lymphoid tissues
are composed of a mosaic of previously unappreciated DC microenvironments that are uniquely
dedicated for the generation of specific programs of T cell immunity. The objective of this grant is to
characterize these innate cell microenvironments during the steady-state and inflammation in both mice and
humans, and to study how they influence adaptive immune responses to vaccines. We will accomplish this goal
in three Specific Aims. In Aim 1, we will perform a comprehensive characterization of DC microenvironments in
mouse and human lymph nodes during the steady-state and after induction of inflammation with distinct vaccine
adjuvants. In Aim 2, we will investigate the molecular mechanisms regulating DC positioning in lymphoid tissues.
In Aim 3, we will interrogate how the spatial organization of DCs influences CD4+ and CD8+ T cell responses
to vaccines. Our rationale is that a better understanding of lymphoid tissue microanatomy, with respect to innate
and adaptive immune cell crosstalk, will help reveal the underlying principles of immune response generation
to vaccines. A long-term goal of our studies is to develop novel approaches to manipulate in vivo cellular
positioning in order to better modulate and fine-tune the innate and adaptive response to vaccines. In summary,
the proposed studies are significant, as they will advance our basic understanding of how immune responses
are generated in vivo, while also promoting development of novel strategies for immunomodulatory therapeutics
and vaccines.
Terms: <2-photon><ATGN><Adaptive Immune System><Address><Adjuvant><Agonist><Antigen-Presenting Cells><Antigens><Assay><Autoregulation><Behavior><Bioassay><Biologic Assays><Biological Assay><Body Tissues><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Immune Function><Chemotaxis><Communication><Cues><Cytometry><Data><Data Set><Dataset><Dendritic Cells><Development><Gene Expression><Generations><Genetic><Goals><Grant><Grips><Heterogeneity><Homeostasis><Human><IMiD><Image><Immune><Immune response><Immune system><Immunes><Immunity><Immunization><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunomodulators><Immunostimulation><In Situ><Individual><Inflammation><Inflammatory><Instruction><Intracellular Communication and Signaling><Link><Location><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic Tissue><Lymphocyte><Lymphocytic><Lymphoid Tissue><Mediating><Mice><Mice Mammals><Microanatomy><Microscopic Anatomy><Microscopy><Modern Man><Molecular><Mosaicism><Murine><Mus><Pathway interactions><Pharmacology><Phenotype><Physiological Homeostasis><Population><Position><Positioning Attribute><Process><Public Health><Racial Segregation><Receptor Protein><Research><Role><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Spleen><Spleen Reticuloendothelial System><Stimulus><T cell response><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Techniques><Testing><Therapeutic><Time><Tissues><Transgenic Organisms><Vaccine Adjuvant><Vaccine Design><Vaccines><Veiled Cells><accessory cell><adaptive immune response><adaptive immunity><allergic/immunologic body system><allergic/immunologic organ system><arm><biological signal transduction><cell type><developmental><effector T cell><experiment><experimental research><experimental study><grasp><host response><imaging><imaging approach><imaging based approach><immune function><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulatory agents><immune modulatory drugs><immunogen><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><improved><in vivo><lymph cell><lymph gland><lymph nodes><mRNA sequencing><mRNA-seq><microbial><mosaic disorders><new approaches><novel><novel approaches><novel strategies><novel strategy><pathway><programs><receptor><response><segregation><social role><thymus derived lymphocyte><tool><transgenic><tumor><two-photon><vaccination study><vaccination trial><vaccine study><vaccine trial>