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Divergent T Cell Phenotypes Define Pediatric Crohn's Disease and Ulcerative Colitis
Leonard Nettey1,2,3,4,5, Hengqi Betty Zheng6, Joseph C Devlin7
1Program in Immunology, Harvard Medical School, Boston, MA 02115, USA.
Medrxiv : the Preprint Server for Health Sciences
|November 24, 2025
Summary
Pediatric Inflammatory Bowel Disease (IBD) treatment response is linked to T cell shifts. Understanding T helper 17 (TH17) and T follicular helper (TFH) cell activity can predict anti-TNF therapy effectiveness in Crohn
Area of Science:
- Immunology
- Gastroenterology
- Pediatric Medicine
Background:
- Pediatric Inflammatory Bowel Disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), presents significant treatment and prognostic challenges.
- Identifying immune cell states that predict response to therapies like anti-TNF agents is crucial for optimizing pediatric IBD care.
- Current understanding of immune cell roles in pediatric IBD pathogenesis and treatment response remains incomplete.
Purpose of the Study:
- To comprehensively analyze colonic immunology in pediatric CD, UC, and functional gastrointestinal disorders (FGID).
- To elucidate the specific immune cell types and states associated with anti-TNF therapy response in pediatric IBD.
- To investigate the role of T cell activation continua and T cell receptor (TCR) polyreactivity in disease pathogenesis and treatment outcomes.
Main Methods:
- The PREDICT study enrolled 79 treatment-naïve pediatric patients undergoing diagnostic endoscopy.
- Comprehensive transcriptomic, histologic, and serologic analyses were performed on colonic samples.
- Immune cell profiling focused on T cell subsets, including TH1, TH17, and TFH populations, and TCR phenotypes.
Main Results:
- A coordinated shift in the TH1-to-TH17 immune activation continuum among T cells was observed and linked to anti-TNF response in pediatric CD.
- For UC, disease complexity involved both TH17 and TFH biology, with pre-treatment TH17 signaling correlating with anti-TNF resistance.
- Polyreactive TCR phenotypes in UC TFH cells were associated with germinal center activity and IgG1 plasma cells, contrasting with TH17 signatures linked to nonresponse.
Conclusions:
- Distinct T cell-dependent mechanisms drive pediatric CD and UC pathogenesis and treatment response.
- Sustained TH17 signaling in CD and baseline TH17 signaling in UC are implicated in disease pathogenesis.
- These findings support the need for endotype-specific therapeutic strategies in pediatric IBD, moving beyond generalized approaches.
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