Local and circulating cytotoxic CD4⁺ T cells are early markers of disease activity in pediatric Crohn's disease.

Authors

Veronika Niederlova, Kyle Kimler, Hengqi Betty Zheng, Marc Elosua Bayes, Rose Hedderman, Paula Keskula, Iva Pacakova, Jan Vecek, Joshua de Sousa Casal, Andrew Kwong, Leonard Nettey, Zoë Steier, Katarína Kováčová, Brandi Bratrude, Jillian Zavistaski, Wei Keat Lim, Andrea T Hooper, Scott MacDonnell, Nathalie Fiaschi, Zaruhi Hovhannisyan, Ghassan Wahbeh, David Suskind, Lusine Ambartsumyan, Dale Lee, Jan Dobeš, Scott B Snapper, Ondrej Stepanek, Alex K Shalek, Leslie S Kean, Jose Ordovas-Montanes

Published in

medRxiv : the preprint server for health sciences. Jun 26, 2026. Epub Jun 26, 2026.

Abstract

Inflammatory bowel disease (IBD) burden is rising globally, yet only subsets of patients benefit from available therapies, underscoring the need for more precise molecular and cellular stratification. In the PREDICT study, we enrolled treatment-naïve pediatric patients with IBD, alongside disorders of gut-brain interaction (DGBI) controls and healthy donors, and profiled their intestinal and blood-derived T cells using single-cell RNA sequencing (scRNA-seq). Across 107 participants, we identify a unique population of cytotoxic CD4⁺ T cells (CD4 CTL) enriched in the inflamed gut of patients with Crohn's disease (CD) and ulcerative colitis. CD4 CTLs are clonally expanded and express cytotoxic effector molecules and IFNG , consistent with antigen-driven activation. Cell-cell interaction analyses implicate macrophage-derived IL-27 as the top candidate for CD4 CTL differentiation, and IL-27 blockade in a mouse model limits CD4 CTL formation. Notably, elevated CD4 CTL frequencies in gut and peripheral blood at diagnosis are associated with subsequent poor outcome of anti-TNF therapy in pediatric CD. Findings in our identification cohort are validated in an independent cohort and through reanalysis of published datasets. Importantly, we designed a simple flow cytometry panel to isolate blood CD4 ⁺ CXCR6 ⁺ CD27 ^- T cells, which displayed a CD4 CTL transcriptional phenotype. Together, our results link CD4 CTLs to anti-TNF nonresponse and support their potential as an early, blood-accessible biomarker for treatment stratification in pediatric CD.

PMID:
42396287
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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