Language

English

Publication Date

7-15-2026

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI202867

PMID

42262868

PMCID

PMC13367974

PubMedCentral® Posted Date

6-9-2026

PubMedCentral® Full Text Version

Post-print

Abstract

BACKGROUND

Sepsis is a leading cause of morbidity and mortality in critically ill children, yet heterogeneous immune responses complicate the development of targeted therapies and the host immune factors driving sepsis pathobiology remain unclear.

METHODS

We integrated deep immune phenotyping, plasma proteomics, single-cell transcriptomics, and phosphoflow cytometry in a prospective cohort of 88 critically ill children to elucidate the mechanisms underlying immune heterogeneity.

RESULTS

Unsupervised clustering of plasma cytokines identified 3 immunologic subgroups, including a high-severity group (“Group C”) characterized by hypercytokinemia driven by IL-6 and IFN-γ. Group C exhibited distinct alterations in immune cell frequency and activation, with a strong association between hyperinflammatory cytokine signaling and lymphocyte dysfunction. Single-cell RNA-seq revealed transcriptional signatures of T cell activation and metabolic stress, with suppression of a lymphoid protective gene program across CD8+ T cell subsets. Despite increased expression of activation markers, T cell receptor repertoire analysis revealed no dominant clonotypes, consistent with bystander activation. Phosphoflow cytometry demonstrated baseline STAT1/STAT3 hyperactivation in Group C CD8+ T cells, which failed to respond to αCD3/αCD28/αCD49d stimulation.

CONCLUSIONS

These findings define an IL-6/IFN-γ–driven endotype of T cell dysfunction in pediatric sepsis and highlight the JAK/STAT axis as a rational target for immunomodulatory therapy.

FUNDING

K12HD047349, K23GM159013, K08AI135091, R01HD095976, Thrasher Research Fund, Burroughs Wellcome Fund, Immune Deficiency Foundation, Primary Immune Deficiency Treatment Consortium, Barbara Brodsky Foundation, CHOP Research Institute.

Keywords

Humans, Sepsis, Signal Transduction, Child, Female, Child, Preschool, Male, STAT3 Transcription Factor, STAT1 Transcription Factor, Infant, CD8-Positive T-Lymphocytes, Interferon-gamma, Adolescent, Interleukin-6, Bioinformatics, Cellular immune response, Proteomics, Clinical Research, Immunology, Inflammation

Published Open-Access

yes

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