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Early-life human CD8+ T cells exhibit rapid, short-lived effector responses and a unique transcription factor

Nina N Brodsky1,2, Monisha Chakder1,2, Dinesh Babu Uthaya Kumar2

  • 1Pediatrics Department, Yale University School of Medicine, New Haven, CT 06520.

Proceedings of the National Academy of Sciences of the United States of America
|July 28, 2025
PubMed

Insights

Neonatal CD8+ T cells show unique molecular programs for rapid responses to viral infections. These cells have an accelerated effector switch and short-lived program, offering insights into early-life immunity.

Area of Science:

  • Immunology
  • Cellular Biology
  • Neonatal Medicine

Background:

  • Neonates and infants exhibit distinct cellular and clinical responses to viral infections compared to adults.
  • Neonatal CD8+ T cells possess innate-like characteristics and a low activation threshold, but the underlying molecular mechanisms are not fully understood.
  • Early-life immune responses may prioritize minimizing tissue damage, especially during passive maternal antibody-mediated immunity.

Purpose of the Study:

  • To define the unique response characteristics and transcription factor landscape of neonatal human CD8+ T cells.
  • To identify molecular pathways that drive distinct early-life immune responses to viral infections.
  • To explore potential therapeutic targets for modulating viral illnesses in neonates.

Main Methods:

  • Comparative analysis of gene expression and protein markers in neonatal versus adult CD8+ T cells.
  • Assessment of T cell activation, proliferation, cell death, and viability.
  • Investigation of the transcription factor landscape, including TOX and HELIOS expression.

Main Results:

  • Naïve neonatal CD8+ T cells display an accelerated effector switch, with elevated levels of KLRG1, KLRB1, FCER1G, DNAM1, granzymes, TNFα, IL-2, and glycolysis compared to adults.
  • Activated neonatal CD8+ T cells undergo rapid proliferation and cell death, with viability rescued by IL-2 or IL-7.
  • Neonatal CD8+ T cells exhibit a unique transcription factor profile, with high expression of TOX and HELIOS (IKZF2), persisting for at least 2 months postnatally.

Conclusions:

  • Early-life human CD8+ T cells maintain a distinct transcriptional state characterized by an accelerated effector switch and a short-lived effector program.
  • These findings reveal key regulatory nodes governing the unique immunobiology of neonatal CD8+ T cells.
  • Understanding these pathways is crucial for developing strategies to manage viral infections in vulnerable infant populations.

Keywords:
CD8+ T celldifferentiationeffectorneonatetranscription factor

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