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Principal Investigator: Peter The Sage
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $490,142
Funding agency: National Institute of Allergy and Infectious Diseases
Immunity to viral infections of the lung require cooperation between humoral and cellular arms of the immune
system. A newly defined subset of CD8 T cell, called CXCR5+ CD8 T cells, have been identified. CXCR5+ CD8
T cells can gain access to the B cell follicle of lymph nodes and interact with B cells. In settings of chronic
infection these CXCR5+ CD8 T cells may have stem-like potential and can differentiate further into effector CD8
T cells. Therefore, CXCR5+ CD8 T cells may have unique polyfunctionality to control both humoral and cellular
arms of the immune system. However, a fundamental understanding of the functions of CXCR5+ CD8 T cells
is lacking due to a paucity of tools to study these cells in vivo. The object of the proposed studies is to elucidate
the precise roles of CXCR5+ CD8 T cells in regulating cellular and antibody mediated anti-viral immunity during
acute respiratory infections, and to assess intrinsic and extrinsic mechanisms controlling these functions. We
hypothesize that polyfunctional CXCR5+ CD8 T cells restrain humoral immunity yet are essential for cellular
immunity and T cell memory. We also hypothesize that the immune system can fine-tune immunity by altering
CXCR5+ CD8 T cell fates through extrinsic signals from effector Tfh cells, and intrinsic factors such as the
expression of the transcription factor Tbet. To test these hypotheses, we will: 1) assess the roles of CXCR5+
CD8 T cells to control humoral and cellular immunity at distinct times in vivo during viral infection and vaccination
with Influenza and SARS-CoV-2, and 2) assess the roles of extrinsic signals from Tfh cells and intrinsic signals
from Tbet to control CXCR5+ CD8 T cell memory and polyfunctionality. We will pursue these aims using
innovative strategies to identify and perturb CXCR5+ CD8 T cell subsets in vivo during viral infection and
vaccination in intact, polyclonal, mice. These strategies include newly developed CXCR5+ CD8 T cell deleter
and Tfh cell deleter models which facilitate the assessment of functionality during the distinct stages of viral
infection and vaccination. The expected outcome of these studies is an elucidation of the precise functions of,
and mechanisms controlling, CXCR5+ CD8 T cell regulation of humoral and cellular immunity. These studies
are significant because they will lead to a deeper understanding of how the immune system mediates anti-viral
immunity and will provide framework for the development of new therapeutics to enhance anti-viral immunity and
promote vaccine efficacy to influenza and SARS-CoV-2.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Ab response><Acute respiratory infection><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Attenuated Vaccines><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><BLR1><BLR1 gene><Basal Transcription Factor><Basal transcription factor genes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><COVID-19 anti-viral><COVID-19 antiviral><COVID-19 vaccination><COVID-19 virus><COVID19 virus><CXCR-5><CXCR5><Cell Body><Cell Communication and Signaling><Cell Function><Cell Mediated Immunology><Cell Physiology><Cell Process><Cell Signaling><Cell-Mediated Immunity><Cells><Cellular Function><Cellular Immunity><Cellular Physiology><Cellular Process><Chronic><CoV-2><CoV2><Data><Development><Environment><Equilibrium><Evolution><General Transcription Factor Gene><General Transcription Factors><Germinal Center><Goals><Grippe><Humoral Immunities><Immune memory><Immune response><Immune system><Immunity><Immunologic Memory><Immunological Memory><Immunological response><Immunomodulation><Individual><Infection><Influenza><Intracellular Communication and Signaling><Intrinsic factor><LYT3><Link><Live-attenuated Vaccine><Lung><Lung Respiratory System><Lung infections><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><MDR15><Mediating><Memory><Mice><Mice Mammals><Modeling><Molecular><Murine><Mus><Outcome Study><Position><Positioning Attribute><Property><Regulation><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 anti-viral><SARS-CoV-2 antiviral><SARS-CoV-2 vaccination><SARS-CoV2><SARS-CoV2 anti-viral><SARS-CoV2 antiviral><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Structure of germinal center of lymph node><Subcellular Process><T cell regulation><T memory cell><T-Cell Subsets><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><Teff cell><Testing><Transcription Factor Proto-Oncogene><Transcription factor genes><Vaccination><Viral Diseases><Viral Pathogenesis><Virus><Virus Diseases><Wuhan coronavirus><acute infection><anamnestic reaction><anti-viral immunity><antibody biosynthesis><antibody-based immunity><antiviral immunity><arm><balance><balance function><biological signal transduction><chronic infection><coronavirus disease 2019 anti-viral><coronavirus disease 2019 antiviral><coronavirus disease 2019 vaccination><coronavirus disease 2019 virus><coronavirus disease-19 virus><developmental><effector T cell><flu infection><flu virus infection><genetic approach><genetic strategy><hCoV19><host response><immune modulation><immune regulation><immune system response><immunoglobulin biosynthesis><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><inhibiting antibody><innovate><innovation><innovative><live vaccine><live vaccines><lymph gland><lymph nodes><lymphnodes><memory T lymphocyte><migration><nCoV2><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><persistent infection><pulmonary><pulmonary infections><reconstitute><reconstitution><response><restraint><secondary immune response><severe acute respiratory syndrome coronavirus 2 anti-viral><severe acute respiratory syndrome coronavirus 2 antiviral><social role><stem><tool><transcription factor><vaccinate against COVID-19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccine efficacy><viral infection><virus infection><virus pathogenesis><virus-induced disease>