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Principal Investigator: ANDREW W GRIMSON
Organization: CORNELL UNIVERSITY
Fiscal Year: 2020
Award: $400,213
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary /Abstract
Neonates are highly susceptible to infection and respond poorly to vaccination for reasons that are not well
understood. Based on our published data, we believe that neonates are particularly vulnerable to repeat
infections because their naïve CD8+ T cells are intrinsically defective at differentiating into memory CD8+ T cells.
A major goal of this grant is to identify the key gene regulatory networks that underlie cell-intrinsic differences
between neonatal and adult CD8+ T cells. Since microRNAs (miRNAs) are developmentally regulated and
required for CD8+ T cell function, we hypothesized that defective CD8+ T cell memory formation in early life may
be due to differences in miRNA expression patterns between neonatal and adult CD8+ T cells. To test our
hypothesis, we used next generation sequencing to identify mouse miRNAs that are differentially regulated in
neonatal and adult CD8+ T cells throughout the response to infection. Surprisingly, our results indicated that
differences in miRNA expression profiles were most pronounced prior to immunological challenge, suggesting
that developmentally-regulated miRNAs do not operate by altering the fate of effector cells at the peak of the
response. Instead, these miRNAs appear to set the activation threshold prior to infection, causing neonatal
CD8+ T cells to differentiate more rapidly into effector cells and biasing them away from a memory precursor
fate. We are particularly interested in two miRNAs (miR-29 and miR-130), which we believe play a major role in
cell-intrinsic differences that exist between neonatal and adult CD8+ T cells in mice and humans. MiR-130 is
preferentially expressed in neonatal CD8+ T cells and targets a number of genes involved in negative regulation
of T cell proliferation or apoptosis. MiR-29, on the other hand, is more abundant in adult CD8+ T cells and
regulates the expression of transcription factors involved in effector and memory cell differentiation. We propose
that the miR-29/miR-130 axis acts as a developmental rheostat for adjusting the activation threshold of CD8+ T
cells, controlling the balance between rapid effector cells (neonates) and long-lived memory cells (adults). The
main objectives of this proposal are to determine how age-related changes in miR-29 and miR-130 expression
alter the ability of CD8+ T cells to respond to infection (Aim 1); identify the key target genes regulated by miR-
29 and miR-130 prior to activation (Aim 2); and determine whether miR-29 and miR-130 can predict vaccine-
specific CD8+ T cell responses in newborns (Aim 3). Accomplishing these aims will lend support for a new
model describing how miRNAs regulate the CD8+ T cell response to infection, which can lead to novel
therapeutic strategies for enhancing the development of memory CD8+ T cells in early life.
Terms: <0-4 weeks old><21+ years old><Adult><Adult Human><Antigens><Apoptosis><Apoptosis Pathway><BCG immunization><BCG vaccination><BCG-vaccinated><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Bacteria><Basal Transcription Factor><Basal transcription factor genes><Behavior><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Data><Development><Effector Cell><Equilibrium><Experimental Models><Gene Targeting><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Goals><Grant><Human><Immune response><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Impairment><In Vitro><Infection><Inflammation><Laboratories><Lead><Life><Link><Malawi><Memory><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNA Expression Profiling><MicroRNAs><Modeling><Modern Man><Molecular><Murine><Mus><NGS Method><NGS system><Neonatal><Newborn Infant><Newborns><Nyasaland><Pattern><Pb element><Play><Position><Positioning Attribute><Programmed Cell Death><Proliferating><Publishing><Regulator Genes><Role><Schools><Subcellular Process><T cell regulation><T cell response><T memory cell><T-Cell Activation><T-Cell Proliferation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Regulatory Elements><Translating><Tropical Medicine><Universities><Up-Regulation><Upregulation><Vaccination><Vaccines><Virus><Work><adulthood><age dependent><age related><aged><balance><balance function><base><cell behavior><cellular behavior><developmental><differential expression><differentially expressed><global miRNA profiling><heavy metal Pb><heavy metal lead><host response><immunogen><immunoresponse><improved><in vivo><innovate><innovation><innovative><insight><interest><mRNA><memory T lymphocyte><miRNA><miRNA expression profiling><miRNA sequencing><miRNA-seq><miRNAs><micro RNA expression profiling><microRNA sequencing><neonatal immunity><neonate><new drug treatments><new drugs><new therapeutics><new therapy><newborn child><newborn children><next gen sequencing><next generation sequencing><next generation therapeutics><nextgen sequencing><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathogen><predictive biomarkers><predictive marker><predictive molecular biomarker><regulatory gene><response><skills><social role><thymus derived lymphocyte><trans acting element><transcription factor><transcriptional differences><vaccine efficacy>