Aberrant STAT Signaling and T Cell Dysregulation Define a Targetable Pediatric Sepsis Endotype

Authors

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

Document Type

Article

Publication Date

7-15-2026

Comments

This article is the author’s final published version in The Journal of clinical investigation, Volume 136, Issue 14, 2026.

The published version is available at https://doi.org/10.1172/JCI202867. Copyright © 2026, Lindell et al.

Abstract

BACKGROUNDSepsis 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.METHODSWe 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.RESULTSUnsupervised 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.CONCLUSIONSThese 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.FUNDINGK12HD047349, K23GM159013, K08AI135091, R01HD095976, Thrasher Research Fund, Burroughs Wellcome Fund, Immune Deficiency Foundation, Primary Immune Deficiency Treatment Consortium, Barbara Brodsky Foundation, CHOP Research Institute.

Recommended Citation

Lindell, Robert B.; Sayed, Samir U.; Campos Duran, Jose S.; Sheetz, Sydney A.; Babu, Apoorva; Knight, Montana S.; Mauracher, Andrea A.; Hay, Ceire A.; Conrey, Peyton E.; Fitzgerald, Julie C.; Yehya, Nadir; Famularo, Stephen T.; Arroyo, Teresa; Tustin, Richard; Fazelinia, Hossein; Behrens, Edward M.; Teachey, David T.; Forbes Satter, Lisa R.; Freeman, Alexandra F.; Bergerson, Jenna Re; Holland, Steven M.; Leiding, Jennifer W.; Weiss, Scott L.; Hall, Mark W.; Taylor, Deanne M.; Feng, Rui; Wherry, E. John; Meyer, Nuala J.; and Henrickson, Sarah E., "Aberrant STAT Signaling and T Cell Dysregulation Define a Targetable Pediatric Sepsis Endotype" (2026). Department of Pediatrics Faculty Papers. Paper 207.
https://jdc.jefferson.edu/pedsfp/207

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

42262868

Language

English