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Principal Investigator: Michael John Hogan
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $160,205
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
The basis of cellular immunity is the recognition by T cells of foreign peptides in association with major
histocompatibility complex (MHC) proteins on the cell surface. CD8 T cells, the subset most associated with
cytolysis, are conventionally believed to recognize peptides bound to the classical, hyper-polymorphic MHC class
Ia molecules (HLA-A, B, and C in humans); however, a handful of studies have suggested that CD8 T cells can
also recognize pathogen-derived peptides in the context of MHC-E (Qa-1 in mice, HLA-E in humans), a nearly
invariant non-classical MHC-Ib molecule typically associated with the regulation of natural killer cell function. In
limited cases, MHC-E-restricted CD8 T cells have been shown to exert potent antiviral effects, but extremely
little is known about how common these responses are in viral infections, what kinds of effector functions they
generally exhibit, how they are regulated, and what antigen presentation pathways drive them. This proposal will
shed light on this enigmatic aspect of cellular immunity, taking advantage of a recently identified Qa-1-restricted
CD8 T cell epitope from influenza A virus called M-SL9. This epitope drives a CD8 T cell response that is co-
dominant with conventional MHC-Ia-restricted epitopes and in preliminary studies appears to protect mice from
weight loss and clinical severity during flu infection. Aim 1 of this research plan will detail the cellular pathways
by which this model Qa-1-restricted epitope is processed, transported, and presented in flu-infected cells. These
studies will be facilitated by an M-SL9-specific CD8 T cell hybridoma line that acts as a highly sensitive reporter
of M-SL9/Qa-1 presentation. Aim 2 will test the hypothesis that Qa-1-restricted CD8 T cells occur commonly in
viral infections and that they protect the host from severe disease, similarly to MHC-Ia-restricted CD8 T cells. An
immunopeptidomics approach will be used to discover Qa-1 epitopes in the context of influenza A virus and
mouse hepatitis virus 1, a beta-coronavirus in the same family as SARS-CoV-2. An mRNA-based vaccination
strategy will be used to raise CD8 T cells against identified Qa-1 epitopes in mice, followed by a challenge with
the corresponding virus and monitoring of disease severity. These results will illuminate a promising but poorly
understood aspect of the cellular immune response, with potential benefits for the design of new vaccines or
immune therapies against infectious diseases and cancer. This proposal will promote the applicant’s career
goals of initiating an independent research career with a rapid pace of productivity, laying a foundation of valuable
data that will enable several viable follow-up studies, and ultimately gaining better understanding the importance
of unconventional forms of antigen presentation in human health. This study will also take place in a broader
context that prioritizes the applicant’s career development by emphasizing feedback from senior scientists,
mentoring trainees, and engaging with current literature and innovative research on and off campus.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><Active Follow-up><Address><Affinity><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Antigen Presentation><Antigen Presentation Pathway><Antigen Processing and Presentation><Antigenic Determinants><Assay><Autoregulation><Binding><Binding Determinants><Bioassay><Biological Assay><Body Weight decreased><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CMV><COVID-19 virus><COVID19 virus><Cancers><Categories><Cell Body><Cell Function><Cell Line><Cell Mediated Immunology><Cell Physiology><Cell Process><Cell Therapy><Cell surface><Cell-Mediated Immunity><Cell-Mediated Lympholytic Cells><CellLine><Cells><Cellular Function><Cellular Immunity><Cellular Physiology><Cellular Process><Cellular biology><Chemicals><Clinical><CoV-2><CoV2><Code><Coding System><Communicable Diseases><Complex><Coronaviridae><Coronavirus><Cytolysis><Cytolytic T-Cell><Cytomegalovirus><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Cytotoxic cell><Data><Dendritic Cells><Disease><Disorder><ELISA><Enzyme-Linked Immunosorbent Assay><Epitopes><Exhibits><Family><Feedback><Follow-Up Studies><Followup Studies><Foundations><Future><Generations><Genetic Technics><Genetic Techniques><Goals><Grippe><H-2Q1><HCMV><HLA-A><HLA-A gene><HLAA><Health><Histocompatibility Complex><Histocompatibility Complices><Homeostasis><Human><Hybridomas><Immune><Immune Precipitation><Immune mediated therapy><Immune response><Immunes><Immunize><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunoprecipitation><Immunotherapy><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenzavirus A><Investigation><K lymphocyte><Laboratories><Literature><Lung><Lung Respiratory System><Lysis><M mulatta><M. mulatta><Macaca mulatta><Macropain><Macrophage><Macroxyproteinase><Major Histocompatibility Complex><Major Histocompatibility Complices><Malignant Neoplasms><Malignant Tumor><Mammalia><Mammals><Maps><Mentors><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Monitor><Mouse Hepatitis Coronavirus><Mouse Hepatitis Virus><Multicatalytic Proteinase><Murine><Murine Gastroenteritis Virus><Murine hepatitis virus><Mus><Mφ><NK Cells><Names><Natural Killer Cells><ORFs><Open Reading Frames><Orthomyxovirus Type A><Pathway interactions><Peptide Signal Sequences><Peptides><Physiological Homeostasis><Primates><Primates Mammals><Process><Productivity><Prosome><Proteasome><Proteasome Endopeptidase Complex><Protein Coding Region><Proteins><Proteolytic Clipping><Proteolytic Processing><Proteosome><Publishing><Qa-1><Qa-1 Antigen><Qa1><Qed-1><RNA vaccine><RNA-based vaccine><Reading Frames><Reagent><Refractory><Regulation><Reporter><Research><Rhesus Macaque><Rhesus Monkey><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIV><Salivary Gland Viruses><Senior Scientist><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 related corona virus 2><Severities><Severity of illness><Signal Peptide><Signal Sequences><Simian Immunodeficiency Viruses><Sorting><Staining method><Stains><Strains Cell Lines><Subcellular Process><Survey Instrument><Surveys><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell response><T cell targeted therapeutics><T cell therapy><T-Cell Activation><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><Testing><Type A Influenza><VAC-TX><Vaccine Therapy><Vaccines><Veiled Cells><Viral><Viral Diseases><Viral Genome><Virus><Virus Diseases><Weight Loss><Weight Reduction><Wuhan coronavirus><activate T cells><active followup><adaptive immunity><adoptive T cell transfer><adoptive T-cell therapy><beta CoV><beta coronavirus><betaCoV><betacoronavirus><body weight loss><career><career development><cell biology><cell mediated therapies><cell type><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><conference><convention><corona virus><coronavirus disease 2019 virus><coronavirus disease-19 virus><cultured cell line><cytokine><cytomegalovirus group><design><designing><disease severity><enzyme linked immunoassay><experiment><experimental research><experimental study><experiments><fighting><flu><flu infection><flu serotype><flu strain><flu subtype><flu viral strain><flu virus infection><flu virus strain><follow up><follow-up><followed up><followup><hCoV19><host response><human pathogen><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunization strategy><immuno therapy><immunogenic><immunogenicity><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza serotype><influenza strain><influenza subtype><influenza viral strain><influenza virus infection><influenza virus strain><influenzavirus><inhibitor><innovate><innovation><innovative><interest><killer T cell><mRNA><mRNA vaccine><mRNA-based vaccine><malignancy><model of animal><mouse model><multicatalytic endopeptidase complex><murine hepatitis coronavirus><murine model><nCoV2><name><named><naming><neoplasm/cancer><new vaccines><next generation vaccines><novel><novel vaccines><pathogen><pathway><plasmid vaccine><polypeptide><prevent><preventing><protein complex><protein signal sequence><pulmonary><respiratory virus><response><summit><symposia><symposium><tandem mass spectrometry><therapeutic T-cell platform><therapeutic vaccination><thymus derived lymphocyte><vaccination strategy><vector vaccine><viral infection><virus genome><virus infection><virus-induced disease><wt-loss><β CoV><β coronavirus><βCoV>