Multi-modal skin atlas identifies a multicellular immune-stromal community associated with disrupted cornification and specific T cell expansion in atopic dermatitis

Evgenij Fiskin^#¹, Gökcen Eraslan^#^{1

2}, Maria B Alora-Palli^#³, Tanvi Jain^#¹, Juan Manuel Leyva-Castillo⁴, Sean Kim⁵, Heather Choe⁵, Caleb A Lareau^{6

7}, Helena Lau⁵, Emily P Finan¹, Isabella Teixeira-Soldano¹, Brenna LaBere^{4

8}, Anne Chu⁴, Brian Woods⁴, Janet Chou⁴, Michal Slyper¹, Julia Waldman¹, Sabina Islam⁹, Lynda Schneider⁴, Wanda Phipatanakul⁴, Craig Platt⁴, Orit Rozenblatt-Rosen^{1

2}, Toni M Delorey¹, Orr Ashenberg¹, Jacques Deguine¹, Gideon P Smith³, Raif S Geha¹⁰, Aviv Regev^{11

12

13}, Ramnik J Xavier^{14

15

16}

Affiliations

¹ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
² Genentech, South San Francisco, CA, USA.
³ Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Departments of Pathology, Stanford University, Stanford, CA, USA.
⁷ Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Division of Pulmonology, Section of Allergy-Immunology, Phoenix Children's Hospital, Phoenix, AZ, USA.
⁹ Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. raif.geha@childrens.harvard.edu.
¹¹ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. aviv.regev.sc@gmail.com.
¹² Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA. aviv.regev.sc@gmail.com.
¹³ Genentech, South San Francisco, CA, USA. aviv.regev.sc@gmail.com.
¹⁴ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁵ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁶ Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.

^# Contributed equally.

PMID: 41741455
DOI: 10.1038/s41467-026-69587-7

Free article

Multi-modal skin atlas identifies a multicellular immune-stromal community associated with disrupted cornification and specific T cell expansion in atopic dermatitis

Evgenij Fiskin et al. Nat Commun. 2026.

Free article

. 2026 Feb 25.

doi: 10.1038/s41467-026-69587-7. Online ahead of print.

Authors

Affiliations

¹ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
² Genentech, South San Francisco, CA, USA.
³ Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Departments of Pathology, Stanford University, Stanford, CA, USA.
⁷ Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸ Division of Pulmonology, Section of Allergy-Immunology, Phoenix Children's Hospital, Phoenix, AZ, USA.
⁹ Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. raif.geha@childrens.harvard.edu.
¹¹ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. aviv.regev.sc@gmail.com.
¹² Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA. aviv.regev.sc@gmail.com.
¹³ Genentech, South San Francisco, CA, USA. aviv.regev.sc@gmail.com.
¹⁴ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁵ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.
¹⁶ Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. xavier@molbio.mgh.harvard.edu.

^# Contributed equally.

PMID: 41741455
DOI: 10.1038/s41467-026-69587-7

Abstract

In atopic dermatitis (AD), skin barrier and immune dysfunction result in chronic tissue inflammation, yet our understanding of the tissue ecosystem remains incomplete. Here, we generate a multi-modal census of 280,518 cells from whole skin tissue samples from 17 adults, including 11 AD patients, integrating it with 430,186 cell profiles from four previous studies into a comprehensive human skin cell atlas. Reconstruction of keratinocyte differentiation revealed disrupted cornification in AD associated with signals from an immune and stromal multicellular community - comprising MMP12⁺ and migratory dendritic cells (DCs), cycling innate lymphoid cells (ILC), natural killer cells, inflammatory CCL19⁺ IL4I1⁺ fibroblasts, and clonally expanded IL13⁺IL22⁺IL26⁺ T cells connected by intercellular feedback loops predicted to impact community assembly. Subsets from this community, along with disrupted cornified keratinocytes, were enriched in GWAS, suggesting that dysfunction in this communication network may initiate AD. Our work highlights disease-associated cell subsets and interactions in chronic skin inflammation.

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Conflict of interest statement

Competing interests: A.R. was a founder and equity holder of Celsius Therapeutics, is an equity holder in Immunitas Therapeutics, and until 31 July 2020 was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and ThermoFisher Scientific. From 1 August 2020, A.R. is an employee of Genentech, a member of the Roche Group, with equity in Roche. R.J.X. is a co-founder of Celsius Therapeutics, Jnana Therapeutics, and director of Moonlake Immunotherapeutics. R.J.X. is an SAB member of Magnet Biomedicine and of Nestlé. From 19 October 2020 to 4 April 2022, respectively, O.R.-R. and G.E. are employees of Genentech, a member of the Roche Group, and have equity in Roche. The remaining authors declare no competing interests.

Update of

Multi-modal skin atlas identifies a multicellular immune-stromal community associated with altered cornification and specific T cell expansion in atopic dermatitis.
Fiskin E, Eraslan G, Alora-Palli MB, Leyva-Castillo JM, Kim S, Choe H, Lareau CA, Lau H, Finan EP, Teixeira-Soldano I, LaBere B, Chu A, Woods B, Chou J, Slyper M, Waldman J, Islam S, Schneider L, Phipatanakul W, Platt C, Rozenblatt-Rosen O, Delorey TM, Deguine J, Smith GP, Geha R, Regev A, Xavier R. Fiskin E, et al. bioRxiv [Preprint]. 2023 Oct 31:2023.10.29.563503. doi: 10.1101/2023.10.29.563503. bioRxiv. 2023. Update in: Nat Commun. 2026 Feb 25. doi: 10.1038/s41467-026-69587-7. PMID: 37961084 Free PMC article. Updated. Preprint.

References

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Multi-modal skin atlas identifies a multicellular immune-stromal community associated with disrupted cornification and specific T cell expansion in atopic dermatitis

Affiliations

Multi-modal skin atlas identifies a multicellular immune-stromal community associated with disrupted cornification and specific T cell expansion in atopic dermatitis

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous