Cytotoxic CD4+ T cells induce age-associated myelopoiesis through CCL5–CCR5 signaling

Abstract Age-associated hematopoietic skewing results in an increase in the neutrophil-to-lymphocyte ratio, which serves as a strong predictor of all-cause mortality in older adults, although its causes are incompletely understood. Here we show that cytotoxic CD4 + T lymphocytes accumulate in the bone marrow of mice during aging and induce myelopoiesis, increasing the neutrophil-to-lymphocyte ratio. T cell receptor-dependent induction of mitochondrial stress and activation of STING upregulates the chemokine CCL5 in CD4 + T lymphocytes. During aging, hematopoietic stem cells and downstream myeloid progenitors upregulate CCR5, the primary receptor for CCL5. Genetic ablation of Ccr5 in hematopoietic progenitors mitigates T cell-induced myeloid skewing and neutrophil expansion. Pharmacological blockade of CCR5 using the Food and Drug Administration-approved drug maraviroc normalizes myelopoiesis, reduces circulating and tissue-infiltrating neutrophils, and improves multiple aging-related biomarkers and functional outcomes in aged mice. Together, these findings demonstrate a T cell–bone marrow axis that exacerbates age-associated decline and highlight CCR5 inhibition as a potential geroprotective strategy.

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Publication Details

Journal
Nature Aging
Published
2026-08-26
DOI
https://doi.org/10.1038/s43587-026-01209-9
Primary Topic
Immune cells in cancer
Type
article
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0.00

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article

Cytotoxic CD4+ T cells induce age-associated myelopoiesis through CCL5–CCR5 signaling

Virginia Zorita, Olaia Naveiras, Camilla Bean, Françoise Solly et al.
Nature Aging
Immune cells in cancer
article

Cytotoxic CD4+ T cells induce age-associated myelopoiesis through CCL5–CCR5 signaling

Virginia Zorita, Olaia Naveiras, Camilla Bean, Françoise Solly, Santos Mañes, Elisa Carrasco, Marı́a Mittelbrunn, César Cobaleda, Gabriela Desdín-Micó, Rafael de Cabo, Myriam Gorospe, Amanda Garrido, Manuel M. Gómez de las Heras, Carlos Anerillas, Valentin Basset, Enrique Gabandé‐Rodríguez, Jorge Martínez-Cano, Isaac Francos-Quijorna, Т. А. Смирнова, José Ignacio Escrig-Larena, Andrea Cugurra, Manolis Pasparakis, Matteo Iannacone, Gonzalo Soto‐Heredero, Eva María Blanco, Sandra Delgado-Pulido, Pablo Ramírez-Ruiz de Erenchun, Elia Winand-Osete, Álvaro Fernández-Almeida, Alice Leandri
article en

Abstract

Abstract Age-associated hematopoietic skewing results in an increase in the neutrophil-to-lymphocyte ratio, which serves as a strong predictor of all-cause mortality in older adults, although its causes are incompletely understood. Here we show that cytotoxic CD4 + T lymphocytes accumulate in the bone marrow of mice during aging and induce myelopoiesis, increasing the neutrophil-to-lymphocyte ratio. T cell receptor-dependent induction of mitochondrial stress and activation of STING upregulates the chemokine CCL5 in CD4 + T lymphocytes. During aging, hematopoietic stem cells and downstream myeloid progenitors upregulate CCR5, the primary receptor for CCL5. Genetic ablation of Ccr5 in hematopoietic progenitors mitigates T cell-induced myeloid skewing and neutrophil expansion. Pharmacological blockade of CCR5 using the Food and Drug Administration-approved drug maraviroc normalizes myelopoiesis, reduces circulating and tissue-infiltrating neutrophils, and improves multiple aging-related biomarkers and functional outcomes in aged mice. Together, these findings demonstrate a T cell–bone marrow axis that exacerbates age-associated decline and highlight CCR5 inhibition as a potential geroprotective strategy.

Nature Aging
National Institutes of Health (US), Consejo Superior de Investigaciones Científicas (ES), University of Padua (IT), Vita-Salute San Raffaele University (IT), Spanish National Centre for Cardiovascular Research (ES), Veneto Institute of Molecular Medicine (IT), Saint Camillus International University of Health and Medical Sciences (IT), Centro Nacional de Biotecnología (ES), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Institute on Aging (US), National Institute on Aging (US), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Centro de Biología Molecular Severo Ochoa (ES), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), Universidad Autónoma de Madrid (ES), University of Lausanne (CH)
National Science Foundation, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Universidad Autónoma de Madrid, Ministerio de Ciencia e Innovación, National Institutes of Health, Agencia Estatal de Investigación, National Institute on Aging
Good health and well-being
Openalex Percentile: Top 16%
Immune cells in cancer
DOIOpen Access PDFOpenAlex
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