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ResearchIn-Press PreviewAgingImmunology Open Access | 10.1172/jci.insight.187271

The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation

Cody S. Nelson,1 Manuel A. Podestà,1 Maya G. Gempler,1 Jeong-Mi Lee,1 Cole J. Batty,2 Peterson G. Mathenge,2 Asra Sainju,2 Matthew R. Chang,2 Hanzhong Ke,2 Pragya Chandrakar,1 Elsa Bechu,1 Sierra Richardson,1 Cecilia B. Cavazzoni,1 Stefan G. Tullius,3 Reza Abdi,1 Musie Ghebremichael,4 Marcia C. Haigis,5 Wayne A. Marasco,2 and Peter T. Sage1

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Nelson, C. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Podestà, M. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Gempler, M. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Lee, J. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Batty, C. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Mathenge, P. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Sainju, A. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Chang, M. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Ke, H. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Chandrakar, P. in: JCI | PubMed | Google Scholar |

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Bechu, E. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Richardson, S. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Cavazzoni, C. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Tullius, S. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Abdi, R. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Ghebremichael, M. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Haigis, M. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Marasco, W. in: JCI | PubMed | Google Scholar

1Transplantation Research Center, Division of Renal Medicine, Department of , Brigham and Women’s Hospital, Boston, United States of America

2Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Boston, United States of America

3Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

4Ragon Institute of MGH, MIT, and Harvard, Cambridge, United States of America

5Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, United States of America

Find articles by Sage, P. in: JCI | PubMed | Google Scholar |

Published March 4, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.187271.
Copyright © 2025, Nelson et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 4, 2025 - Version history
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Abstract

Humoral immunity is orchestrated by follicular helper T (Tfh) cells, which promote cognate B cells to produce high-affinity, protective antibodies. In aged individuals, humoral immunity after vaccination is diminished despite the presence of Tfh cells, suggesting defects after initial Tfh formation. In this study, we utilized both murine and human systems to investigate how aging alters Tfh cell differentiation after influenza vaccination. We found that young Tfh cells underwent progressive differentiation after influenza vaccination, culminating in clonal expansion of effector-like cells in both draining lymph nodes and blood. In aging, early stages of Tfh development occurred normally. However, aging rewired the later stages of development in Tfh cells, resulting in a transcriptional program reflective of cellular senescence, sustained pro-inflammatory cytokine production, and metabolic reprogramming. We investigated the extent to which this rewiring of aged Tfh cells is due to the age-associated inflammatory (“inflammaging”) microenvironment and found that this setting was sufficient to both block the transition of Tfh cells to a post-effector resting state and to skew Tfh cells towards the age-rewired state. Together, these data suggest that aging dampens humoral immunity by cytokine-mediated rewiring of late effector Tfh cell differentiation into an activated, yet less functional, cellular state.

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