A unified network systems approach uncovers a core program underlying T follicular helper cell differentiation
Characterizing multi-scale processes underlying immune-state progression is critical for defining their function. This becomes pertinent for functionally diverse and plastic immune cells, such as T follicular helper (Tfh) cells. Here, we adopt a multi-scale network-systems approach that incorporates both regulatory and protein-protein interactions. This approach integrates diverse data types, captures regulation across levels of immune system organization, and recapitulates known Tfh differentiation drivers. Further, we present CoreNet, a core Tfh gene set that is conserved between humans and mice, across tissue types and disease contexts, and is consistent across data modalities. Using CoreNet, we implicate NR3C1 and interleukin (IL)-12 in the regulation of Tfh differentiation. Notably, IL-12 is permissive for differentiation of Tfh precursors but blocks differentiation into germinal center Tfh cells. Overall, this work elucidates networks with unexplored roles governing Tfh differentiation across species and tissues, while providing a generalizable framework. CoreNet is accessible through an interactive web server: https://pitt-csi.shinyapps.io/tfhcorenet/. Follicular helper T (TFH) cells are functionally diverse and plastic. Here, using a multi-scale approach integrating multi-omic data with regulatory and protein networks, the authors present a core gene network involved in TFH differentiation, which is conserved across species, tissues and disease.
Authors
- Tracy Tabib (ORCID: https://orcid.org/0000-0003-4053-988X)
- Susan Pereira Ribeiro (ORCID: https://orcid.org/0000-0002-3127-3138)
- Amanda C. Poholek (ORCID: https://orcid.org/0000-0002-5587-8940)
- Perla M. Del Río Estrada (ORCID: https://orcid.org/0000-0003-3366-3268)
- Dafne Díaz Rivera (ORCID: https://orcid.org/0000-0001-6335-455X)
- Maribel Soto-Nava (ORCID: https://orcid.org/0000-0001-5405-8855)
- Vinay S. Mahajan (ORCID: https://orcid.org/0000-0003-0814-2989)
- Grace J. Yuen (ORCID: https://orcid.org/0000-0002-3253-9575)
- Vinay Viswanadham (ORCID: https://orcid.org/0000-0002-0236-6490)
- Rebecca A. Elsner (ORCID: https://orcid.org/0000-0001-5364-8060)
- Alisa A. Omelchenko (ORCID: https://orcid.org/0000-0002-1299-4693)
- Shiv Pillai (ORCID: https://orcid.org/0000-0002-9905-875X)
- Jishnu Das (ORCID: https://orcid.org/0000-0002-5747-064X)
- Mark J. Shlomchik (ORCID: https://orcid.org/0000-0002-2152-0959)
- Gonzalo Salgado-Montes de (ORCID: https://orcid.org/0000-0002-5735-8607)
- Valentino D’Onofrio (ORCID: https://orcid.org/0000-0003-3828-0442)
- Na Sun (ORCID: https://orcid.org/0000-0001-9653-3482)
- Swapnil Keshari (ORCID: https://orcid.org/0000-0001-6451-9432)
- Sudhir P. Kasturi
- Lady Ruiz-Carbajal
- Hamid Mattoo
- Alyson Wang (ORCID: https://orcid.org/0009-0007-8246-6697)
- Yijia Chen
- Chinmay V. Gadiraju
- Syed A. Rahman
- Santiago Ávila-Ríos
Institutions
- Brigham and Women's Hospital (US)
- Feinstein Institute for Medical Research (US)
- Harvard University (US)
- Emory University (US)
- University of Pittsburgh (US)
- Ghent University Hospital (BE)
- Ragon Institute of MGH, MIT and Harvard (US)
- Instituto Nacional de Enfermedades Respiratorias (MX)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-22
- DOI
- https://doi.org/10.1038/s41467-026-75559-8
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00