Aberrant STAT signaling and T cell dysregulation define a targetable pediatric sepsis endotype

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 three 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 sequencing 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 Foundation, Burroughs Wellcome Fund CAMS, Immune Deficiency Foundation, Primary Immune Deficiency Treatment Consortium, Barbara Brodsky Foundation, CHOP Research Institute.

Authors

Institutions

Publication Details

Journal
Journal of Clinical Investigation
Published
2026-06-09
DOI
https://doi.org/10.1172/jci202867
Primary Topic
Sepsis Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Aberrant STAT signaling and T cell dysregulation define a targetable pediatric sepsis endotype

Montana Knight, Lisa Forbes Satter, Sarah E. Henrickson, Robert B. Lindell et al.
Journal of Clinical Investigation
Sepsis Diagnosis and Treatment
article

Aberrant STAT signaling and T cell dysregulation define a targetable pediatric sepsis endotype

Montana Knight, Lisa Forbes Satter, Sarah E. Henrickson, Robert B. Lindell, Hossein Fazelinia, Nuala J. Meyer, Steven M. Holland, Apoorva Babu, Peyton Conrey, Jenna Bergerson, Jennifer W. Leiding, Rui Feng, Ceire A. Hay, Richard Tustin, Sydney A. Sheetz, Stephen T. Famularo, J C Fitzgerald, N Yehya, Jose S Campos Duran, E. John Wherry, Edward M. Behrens, Deanne M. Taylor, Alexandra F. Freeman, David T. Teachey, Mark W. Hall, Andrea A. Mauracher, Teresa Arroyo, Samir U. Sayed, Scott L. Weiss
article en

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 three 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 sequencing 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 Foundation, Burroughs Wellcome Fund CAMS, Immune Deficiency Foundation, Primary Immune Deficiency Treatment Consortium, Barbara Brodsky Foundation, CHOP Research Institute.

Journal of Clinical Investigation
Nationwide Children's Hospital (US), Children's Hospital of Philadelphia (US), Johns Hopkins University (US), Thomas Jefferson University (US), Baylor College of Medicine (US), Johns Hopkins Medicine (US), Parker Institute for Cancer Immunotherapy (US), National Institute of Allergy and Infectious Diseases (US), Texas Children's Hospital (US), University of Pennsylvania (US)
Burroughs Wellcome Fund, Immune Deficiency Foundation, Thrasher Research Fund, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 7%
Sepsis Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.