# Targetable pathways driving sub-optimal early-life CD8 T cell responses

> **NIH NIH K08** · YALE UNIVERSITY · 2024 · $195,068

## Abstract

PROJECT SUMMARY
Severe infection is one of the top three causes of neonatal mortality, according to the World Health Organization.
Of infection-related deaths, viruses cause 6.5% in neonates and 19.4% in infants. In children under five years of
age, infections with respiratory syncytial virus account for particularly high morbidity and mortality rates. There
is an unmet need to understand better and modulate the unique biology of early childhood immune cells,
including cytotoxic CD8 T cells that act as a double-edged sword by protecting from intracellular pathogens
including viruses while also contributing to immunopathology during severe viral bronchiolitis. The functional
properties and the molecular basis for the unique features and remodeling of CD8 T cells in early childhood
remain largely undefined in humans, limiting the advancement of therapeutic modulators. Neonates have lower
CD8 T counts than adults, and their CD8 T cells have a shorter life span. Moreover, studies in the field have
found that neonatal CD8 T cells undergo rapid proliferation and terminal differentiation as effector cells at the
expense of forming long-lived memory cells. Both neonates and patients with an immune deficiency called
Activated PI3K-Delta Syndrome (APDS) suffer from severe viral infections and have similarly atypical CD8 T cell
function. We hypothesize that early-life CD8 T cells have a decreased threshold for PI3K/mTOR activation, which
enhances effector activity and augments short-lived effector cytotoxic T cell fates that can contribute to
immunopathology in severe viral bronchiolitis. By comparing human neonatal, child, young adult, and moderate
vs. severe RSV bronchiolitis patient CD8 T cells in vitro, Aim 1 will define mechanisms driving increased
proliferation, glycolysis, and cell death in early-life CD8 T cells and Aim 2 will determine roles of PI3K/mTOR
pathways in T cell function during RSV bronchiolitis and their relationship with disease severity. This research
will lead to further insights into how early-life CD8 T cells differ functionally from those of adults and what pathways
could serve as targets for interventions to improve immune responses and outcomes of severe early-life
infection.
Nina Brodsky, M.D., is an Assistant Professor in Pediatric Critical Care at Yale University School of Medicine.
Her career goal is to become an independent principal investigator leading translational research efforts and to
become proficient in developing targeted translational therapies to improve outcomes for patients who suffer
from severe infection and immune-mediated diseases. This career development award will allow Dr. Brodsky to
1) hone her skills in immunologic, omics, and translational research methods under the direction of a mentoring
team that is at the forefront of research in T cell function, signaling and metabolism and 2) identify promising
molecular targets for intervention to improve outcomes of severe infection for her future research.

## Key facts

- **NIH application ID:** 10887226
- **Project number:** 1K08AI177743-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nina Brodsky
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,068
- **Award type:** 1
- **Project period:** 2024-08-02 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887226

## Citation

> US National Institutes of Health, RePORTER application 10887226, Targetable pathways driving sub-optimal early-life CD8 T cell responses (1K08AI177743-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10887226. Licensed CC0.

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