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Principal Investigator: E. John Wherry
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $356,453
Funding agency: National Institute of Allergy and Infectious Diseases
Project Abstract
Human immunology has changed radically in the past decade, accelerated, in part, by the COVID-19 pandemic.
Despite this progress, we still lack knowledge of how to specifically induce optimal vaccine-induced T and B cell
responses. One major gap in human immunology is the inability to precisely interrogate individual immune
pathways in antigen-specific T and B cell responses through gain- or loss-of-function. Such studies have
remained largely the domain of mouse immunology. However, humans are routinely treated with specific immune
modifying therapeutics. Many of these same individuals also receive vaccines that allow examination of a specific
adaptive immune response with known timing and well-defined antigens. Thus, it is now possible to capture the
human experiment where the human immune system has been specifically perturbed by a therapeutic while
another immune stimulus, such as a vaccine, is delivered. With well-designed patient cohorts selected for receipt
of drugs that target a pathway of interest, key mechanistic gain- and loss-of-function type studies can be
performed in humans. Here, we focus on the PD-1 inhibitory receptor pathway and vaccine-induced immunity.
PD-1 is highly expressed in germinal centers (GC) by GC T follicular helper (TFH) cells, and the PD-1 ligands
PD-L1 and PD-L2 are expressed by GC B cells. PD-1 is also upregulated by activated CD8 T cells during priming
in humans. The role of the PD-1 pathway in human vaccine immunity, however, is largely unknown. Our
preliminary data generated during the previous U19 cycle demonstrate the feasibility of this approach with
promising data on effects of PD-1 on vaccine-induced TFH responses. Thus, the studies proposed will address a
major gap in knowledge in human immunology: how does PD-1, expressed highly by vaccine induced immune
cells, regulate vaccine-induced humoral and cellular immunity. We will test the central hypothesis that disruption
of the PD-1 pathway through precision immunotherapy leads to changes in magnitude, differentiation state,
repertoire, quality, and memory for GC-dependent TFH and B cell responses as well as GC-independent CD8 T
cell responses. First, we will test whether loss of PD-1 signals alters the quality and/or magnitude of GC-
associated CD4 T cell and B cell responses to vaccination. Second, we will ask whether loss of PD-1 signals
alters CD8 T cell priming, repertoire and memory CD8 T cell differentiation following vaccination. This work will
provide new insights into how a key immune regulatory pathway controls vaccine induced immunity using
“mouse-like” loss-of-function studies in humans. This work will have implications for improving vaccines and for
the fundamental regulation of immunological memory in humans. Moreover, this approach could be a platform
for future studies capturing specific human immune perturbation to interrogate new immunobiology. By its nature
Project 3 will be highly interactive with Project 1 and 2 and all Cores. Core B will generate samples used in this
Project, and this Project will use Core C services. Projects 1, 2 and 3 will synergize and interact extensively to
understand PD-1-based immune perturbation in humans.
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Targeting><FNA><Fine Needle Aspirate><Fine needle aspiration biopsy><Fine-Needle Aspiration><Flu vaccination><Future><Gene Transcription><Genetic Transcription><Germinal Center><Grippe><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Humoral Immunities><Immune><Immune mediated therapy><Immune memory><Immune response><Immune system><Immunes><Immunity><Immunobiology><Immunologic Memory><Immunological Memory><Immunological response><Immunologically Directed Therapy><Immunology><Immunomodulation><Immunophysiology><Immunotherapy><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Influenza><Influenza immunization><Influenza vaccination><Intracellular Communication and Signaling><Knowledge><Ligands><Malignant Neoplasms><Malignant Tumor><Memory><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Modality><Modern Man><Murine><Mus><Nature><PD 1><PD-1><PD-1 checkpoint pathway><PD-1 inhibitors><PD-1 pathway><PD-1 signaling pathway><PD-L1><PD1><PD1 checkpoint pathway><PD1 inhibitors><PD1 pathway><PD1 signaling pathway><PDL-1><PDL1><Pathway interactions><Patients><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Prophylactic vaccination against influenza><RNA Expression><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Receptor Protein><Regulatory Pathway><Research Design><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Services><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress 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