DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation

Jennifer Niven; Salih  Kucuk; Atrayee  Gope; Michelangelo  Certo; Fearon C. Cassidy; Ainhoa Arana Echarri; Sadaf Ali; Efthymios  Ladoukakis; Sofia Vidali; Chiara  Macchi; Sayeda S  Amir; Ronan  Bergin; Sophie Davies; Oliver J. Perkin; Joanne Smith; Danilo  Cucchi; Helen Heneghan; Susanne N. Wijesinghe; Benjamin J. Jenkins; Shanat  Baig; Christopher  Mahony; Chiamaka  Chidomere; Sovan  Sarkar; Anna  Nicolaou; Jorge  Caamaño; Adam Croft; Edward Davies; Dylan Thompson; Donal  O'Shea; Simon W. Jones; Niharika A. Duggal; Massimiliano  Ruscica; Maria Makarova; Nicholas Jones; Gabriela  Da Silva Xavier; Tarekegn  Geberhiwot; James Turner; Andrew E. Hogan; Belinda  Nedjai; Claudio Mauro

doi:10.1038/s44319-026-00765-w

DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation

Jennifer Niven
, Salih Kucuk
, Atrayee Gope
, Michelangelo Certo
, Fearon C. Cassidy
, Ainhoa Arana Echarri
, Sadaf Ali
, Efthymios Ladoukakis
, Sofia Vidali
, Chiara Macchi
, Sayeda S Amir
, Ronan Bergin
, Sophie Davies
, Oliver J. Perkin
, Joanne Smith
, Danilo Cucchi
, Helen Heneghan
, Susanne N. Wijesinghe
, Benjamin J. Jenkins
, Shanat Baig

Christopher Mahony, Chiamaka Chidomere, Sovan Sarkar, Anna Nicolaou, Jorge Caamaño, Adam Croft, Edward Davies, Dylan Thompson, Donal O'Shea, Simon W. Jones, Niharika A. Duggal, Massimiliano Ruscica, Maria Makarova, Nicholas Jones, Gabriela Da Silva Xavier, Tarekegn Geberhiwot, James Turner, Andrew E. Hogan, Belinda Nedjai, Claudio Mauro

University of Birmingham
Karolinska Institutet
Maynooth University
University Hospitals Birmingham NHS Foundation Trust
Queen Mary University, London
University of Milan
Swansea University
University of Manchester
Royal Orthopaedic Hospital
University College Dublin
Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico
NIHR Birmingham Biomedical Research Centre

Research output: Contribution to journal › Article › peer-review

Abstract

Obesity represents a major global healthcare crisis, with childhood obesity rising at an alarming rate. Children with obesity are highly likely to carry it into adulthood, bringing numerous associated health risks. Even more troubling is the emerging understanding of “obesity memory”, which contributes to the frequent issue of weight regain. Here, we show that obesity imprints CD4 T cells through DNA methylation, leading to a long-time lag, spanning years, before adaptive immune homeostasis is restored after weight loss. Differential DNA methylation analysis highlights autophagy and immune senescence as potential key mechanisms underpinning this memory of obesity in CD4 T cells. In addition, particularly palmitate could be a key saturated fatty acid that can contribute to epigenetic alterations in CD4 T cells, potentially perpetuating this altered state. We identify molecular candidates (i.e., Stk26 and Cdkn1c) underpinning key cell functions (autophagy and immune senescence) that could be targeted to promote a return to immune homeostasis alongside weight loss. These findings raise the possibility that targeting such pathways could support the restoration of immune homeostasis alongside weight loss therapies.

Original language	English
Journal	EMBO Reports
Early online date	27 Apr 2026
DOIs	https://doi.org/10.1038/s44319-026-00765-w
Publication status	Published - 27 Apr 2026

Data Availability Statement

All nanostring sequencing data reported in this study have been deposited in the NCIB GEO repository under the GEO accession number GSE300229. The RRBS raw sequence data reported in this study have been deposited in the Genome Sequence Archive in the National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA accession number: CRA027110).

The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44319-026-00765-w.

Acknowledgements

We thank Janet Lord for continuous advice on the progress of the project; Abdullah AlGhamdi for help with blood cone protocols; Mohammad Alqahtani and Mahsa Rahimzadeh for help with processing mouse tissues; Biomedical Service Unit (BMSU) at the University of Birmingham for support with animal work; BACR and NHS Blood Transfusion Centre at the University of Birmingham and Birmingham NHS Trust for support with blood collection.

Funding

C Mauro is supported by a Professorial Research Fellowship by the University of Birmingham, the Medical Research Council Project Grant MR/T016736/1, and the British Heart Foundation Basic Science Research Fellowship FS/SBSRF/22/31031. C Mauro, SWJ, ND, and MR are supported by the Doctorate Training Network Award HORIZON – MSCA – 2024 – DN 101167421. JN is supported by a University of Birmingham British Heart Foundation Accelerator Award. NJ is supported by the Medical Research Council New Investigator Research Grant MR/ X000095/1. SS is supported by the Medical Research Council Project Grant MR/Z504488/1 and Action Medical Research/LifeArc Grant GN3049. SWJ is supported by the Medical Research Council Project Grant MR/W026961/1 and Versus Arthritis grants 21530 and 21812.

Funders
Medical Research Council

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Cite this

Niven, J., Kucuk, S., Gope, A., Certo, M., Cassidy, F. C., Arana Echarri, A., Ali, S., Ladoukakis, E., Vidali, S., Macchi, C., Amir, S. S., Bergin, R., Davies, S., Perkin, O. J., Smith, J., Cucchi, D., Heneghan, H., Wijesinghe, S. N., Jenkins, B. J., ... Mauro, C. (2026). DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation. EMBO Reports. https://doi.org/10.1038/s44319-026-00765-w

Niven, J, Kucuk, S, Gope, A, Certo, M, Cassidy, FC, Arana Echarri, A, Ali, S, Ladoukakis, E, Vidali, S, Macchi, C, Amir, SS, Bergin, R, Davies, S, Perkin, OJ, Smith, J, Cucchi, D, Heneghan, H, Wijesinghe, SN, Jenkins, BJ, Baig, S, Mahony, C, Chidomere, C, Sarkar, S, Nicolaou, A, Caamaño, J, Croft, A, Davies, E, Thompson, D, O'Shea, D, Jones, SW, Duggal, NA, Ruscica, M, Makarova, M, Jones, N, Da Silva Xavier, G, Geberhiwot, T, Turner, J, Hogan, AE, Nedjai, B & Mauro, C 2026, 'DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation', EMBO Reports. https://doi.org/10.1038/s44319-026-00765-w

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abstract = "Obesity represents a major global healthcare crisis, with childhood obesity rising at an alarming rate. Children with obesity are highly likely to carry it into adulthood, bringing numerous associated health risks. Even more troubling is the emerging understanding of “obesity memory”, which contributes to the frequent issue of weight regain. Here, we show that obesity imprints CD4 T cells through DNA methylation, leading to a long-time lag, spanning years, before adaptive immune homeostasis is restored after weight loss. Differential DNA methylation analysis highlights autophagy and immune senescence as potential key mechanisms underpinning this memory of obesity in CD4 T cells. In addition, particularly palmitate could be a key saturated fatty acid that can contribute to epigenetic alterations in CD4 T cells, potentially perpetuating this altered state. We identify molecular candidates (i.e., Stk26 and Cdkn1c) underpinning key cell functions (autophagy and immune senescence) that could be targeted to promote a return to immune homeostasis alongside weight loss. These findings raise the possibility that targeting such pathways could support the restoration of immune homeostasis alongside weight loss therapies.",

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AU - Gope, Atrayee

AU - Certo, Michelangelo

AU - Cassidy, Fearon C.

AU - Arana Echarri, Ainhoa

AU - Ali, Sadaf

AU - Ladoukakis, Efthymios

AU - Vidali, Sofia

AU - Macchi, Chiara

AU - Amir, Sayeda S

AU - Bergin, Ronan

AU - Davies, Sophie

AU - Perkin, Oliver J.

AU - Smith, Joanne

AU - Cucchi, Danilo

AU - Heneghan, Helen

AU - Wijesinghe, Susanne N.

AU - Jenkins, Benjamin J.

AU - Baig, Shanat

AU - Mahony, Christopher

AU - Chidomere, Chiamaka

AU - Sarkar, Sovan

AU - Nicolaou, Anna

AU - Caamaño, Jorge

AU - Croft, Adam

AU - Davies, Edward

AU - Thompson, Dylan

AU - O'Shea, Donal

AU - Jones, Simon W.

AU - Duggal, Niharika A.

AU - Ruscica, Massimiliano

AU - Makarova, Maria

AU - Jones, Nicholas

AU - Da Silva Xavier, Gabriela

AU - Geberhiwot, Tarekegn

AU - Turner, James

AU - Hogan, Andrew E.

AU - Nedjai, Belinda

AU - Mauro, Claudio

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N2 - Obesity represents a major global healthcare crisis, with childhood obesity rising at an alarming rate. Children with obesity are highly likely to carry it into adulthood, bringing numerous associated health risks. Even more troubling is the emerging understanding of “obesity memory”, which contributes to the frequent issue of weight regain. Here, we show that obesity imprints CD4 T cells through DNA methylation, leading to a long-time lag, spanning years, before adaptive immune homeostasis is restored after weight loss. Differential DNA methylation analysis highlights autophagy and immune senescence as potential key mechanisms underpinning this memory of obesity in CD4 T cells. In addition, particularly palmitate could be a key saturated fatty acid that can contribute to epigenetic alterations in CD4 T cells, potentially perpetuating this altered state. We identify molecular candidates (i.e., Stk26 and Cdkn1c) underpinning key cell functions (autophagy and immune senescence) that could be targeted to promote a return to immune homeostasis alongside weight loss. These findings raise the possibility that targeting such pathways could support the restoration of immune homeostasis alongside weight loss therapies.

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U2 - 10.1038/s44319-026-00765-w

DO - 10.1038/s44319-026-00765-w

M3 - Article

SN - 1469-221X

JO - EMBO Reports

JF - EMBO Reports

ER -

DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation

Abstract

Data Availability Statement

Acknowledgements

Funding

UN SDGs

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