Type 2 lymphocytes restrict type 3 lymphocytes during liver fibrosis and colocalize in fibroblast niches
Fibroblasts are dynamic structural cells that direct both beneficial tissue repair and pathological organ fibrosis through interactions with tissue-resident type 2 lymphocytes (T2Ls) and type 3/17 lymphocytes (T3Ls). The cytokines interleukin-13 (IL-13) and IL-17A, produced by T2Ls and T3Ls, respectively, are linked to both tissue inflammation and fibrosis, but how their spatial positioning influences beneficial or pathological organ remodeling remains unclear. Using mouse models of liver injury and fibrosis, three-dimensional microscopy, and spatial transcriptomics, we found an accumulation of periportal and fibrotic tract T2Ls, predominantly group 2 innate lymphoid cells (ILC2s), positioned near T3Ls and niche adventitial fibroblasts and adjacent to discrete profibrotic myofibroblasts. Unexpectedly, T2L ablation worsened both carbon tetrachloride- and bile duct ligation-induced liver fibrosis, accompanied by increased IL-17A<sup>+</sup> T3Ls, predominantly γδ T cells. In contrast, concurrent T2L and T3L ablation reduced liver fibrosis. Our work suggests a spatially associated cross-talk between liver lymphocytes and fibroblast niches that tunes liver repair but can go awry in pathological liver fibrosis.
Authors
- Jun-Hoe Lee (ORCID: https://orcid.org/0000-0002-6331-3472)
- Sofia Caryotakis (ORCID: https://orcid.org/0000-0003-3522-0022)
- Marcela T Taruselli (ORCID: https://orcid.org/0000-0002-7965-4335)
- Nicholas M. Mroz
- Marlene Ganslmeier
- Julia Nilsson (ORCID: https://orcid.org/0000-0001-8170-2167)
- Madelene W. Dahlgren (ORCID: https://orcid.org/0000-0002-8640-0157)
- Aras N. Mattis (ORCID: https://orcid.org/0000-0002-5813-164X)
- Kelly M. Cautivo (ORCID: https://orcid.org/0000-0003-4434-2814)
- Taeeun Gu (ORCID: https://orcid.org/0009-0001-8317-9047)
- Richard M. Locksley (ORCID: https://orcid.org/0000-0002-5468-6867)
- Anna Lu Gan
- Maya E. Kotas (ORCID: https://orcid.org/0000-0002-8102-6346)
- Peri Matatia (ORCID: https://orcid.org/0000-0002-5389-3637)
- Claire E. O’Leary (ORCID: https://orcid.org/0000-0001-9052-4593)
- Johanna Wagner (ORCID: https://orcid.org/0000-0002-2999-6900)
- Anthony A. Chang
- Hyeewon Seo
- Ari B Molofsky
- N Ewing Crystal
- Maria K. McClave
- Hyun Je Kim
- Carlos O. Lizama
- Tien Peng
- Julia Sbierski-Kind
Institutions
- Tufts University (US)
- Howard Hughes Medical Institute (US)
- University of Wisconsin–Madison (US)
- Seoul National University (KR)
- University of California, San Francisco (US)
- Lund University (SE)
- Universitätsklinikum Würzburg (DE)
- Broad Center (US)
- Io Therapeutics (United States) (US)
- German Center for Diabetes Research (DE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Science Advances
- Published
- 2026-03-11
- DOI
- https://doi.org/10.1126/sciadv.aea6805
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Larry L. Hillblom Foundation
- Regeneron Pharmaceuticals
- Deutsche Forschungsgemeinschaft
- Eberhard Karls Universität Tübingen
- Seoul National University
- Vetenskapsrådet
- Ludwig-Maximilians-Universität München
- Genentech
- Liver Center, University of California, San Francisco