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

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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.

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 III, Teresa Arroyo, Richard Tustin III, Hossein Fazelinia, Edward M. Behrens, David T. Teachey, Lisa R. Forbes Satter, Alexandra F. Freeman, Jenna R.E. Bergerson, Steven M. Holland, Jennifer W. Leiding, Scott L. Weiss, Mark W. Hall, Deanne M. Taylor, Rui Feng, E. John Wherry, Nuala J. Meyer, Sarah E. Henrickson