Cytotoxic CD4+ T cells drive aging-related myelopoiesis through CCL5–CCR5 signaling

One of the most consistent hallmarks of aging is a slow but decisive shift in the composition of the blood. Across mammalian species, the hematopoietic system becomes increasingly biased toward the production of myeloid cells—neutrophils, monocytes and macrophages—at the expense of lymphoid lineages. This myeloid skewing fuels a chronic, low-grade inflammatory state that has been implicated in cardiovascular disease, neurodegeneration, frailty and reduced responsiveness to vaccination. A new study published in Nature Aging now identifies a surprising cellular culprit behind this process: cytotoxic CD4+ T cells, an immune population traditionally regarded as helper cells, which appears to actively coax the aged bone marrow into producing more myeloid cells through a well-defined signaling pathway.

The study, summarized in a Research Briefing in Nature Aging by a team led by Estefanía Gabandé-Rodríguez and colleagues, demonstrates that cytotoxic CD4+ T cells that accumulate in the bone marrow with age promote myelopoiesis—the generation of myeloid cells—through the chemokine axis CCL5–CCR5. CCL5, also known as RANTES, is a chemokine secreted by activated T cells, and CCR5 is its receptor, a molecule already famous in immunology as a co-receptor for HIV entry and the target of the clinically approved antiretroviral drug maraviroc. The researchers found that blocking this axis, either genetically or pharmacologically, could partially restore a more youthful balance between lymphoid and myeloid output in aged mice, positioning maraviroc as an unexpected candidate for immune rejuvenation.

The clinical significance of myeloid skewing is underscored by converging evidence from human cohort studies. A 2024 follow-up analysis of the Baltimore Longitudinal Study on Aging reported that the neutrophil-to-lymphocyte ratio, a simple clinical measure that rises as myelopoiesis gains the upper hand, predicts both multimorbidity and all-cause mortality in a cohort of 1,769 older participants. In other words, the degree to which the immune system tips toward myeloid cells is not merely a correlate of aging but appears to carry prognostic weight for health span and survival. Understanding the mechanisms that drive this skewing therefore has implications that extend well beyond basic hematology.

The new work builds on an intriguing earlier observation from cancer immunology. In 2018, researchers reported that T cells become sequestered in the bone marrow of patients with glioblastoma and other intracranial tumors, as well as in tumor-bearing mice, effectively hiding a substantial pool of lymphocytes away from the circulation. The aged bone marrow appears to recapitulate aspects of this phenomenon. As animals and humans grow older, cytotoxic CD4+ T cells increasingly take up residence in the bone marrow niche, where they sit in close proximity to hematopoietic stem and progenitor cells, the factories from which all blood cell lineages emerge. What those T cells do once they arrive has now been clarified.

The mechanistic story revealed by the study centers on CCL5 secretion. Cytotoxic CD4+ T cells in the aged marrow produce abundant CCL5, which engages CCR5 expressed on hematopoietic stem and progenitor cells. This signaling input pushes the differentiation program of the progenitors toward the myeloid lineage, amplifying the production of neutrophils and monocytes while constraining lymphoid output. The researchers demonstrated that interfering with this axis ameliorates the age-associated hematopoietic dysfunction that accompanies the accumulation of cytotoxic CD4+ T cells. Notably, treatment with maraviroc—a drug already in the clinic, with a well-characterized safety profile from two decades of use in HIV therapy—was able to rebalance immunity in aged mice, offering a plausible route to clinical translation.

The finding resonates strongly with parallel work in autoimmune disease. A 2022 study in Cell showed that bone marrow hematopoiesis drives the progression of multiple sclerosis, and that autoreactive CD4+ T cells fuel this process by secreting CCL5, thereby driving myelopoiesis during autoimmune neuroinflammation. The new study effectively extends that paradigm from pathological inflammation to physiological aging: the same molecular circuit that autoreactive T cells exploit to escalate neuroinflammation appears to operate quietly in the aged marrow, where cytotoxic CD4+ T cells gradually remodel the composition of the blood. Aging, in this view, co-opts an inflammatory program normally associated with disease.

The role of cytotoxic CD4+ T cells in aging is, however, far from one-dimensional, and the authors situate their findings within a rapidly evolving literature. Recent work has shown that CD4+ cytotoxic T lymphocytes can eliminate senescent cells—damaged, growth-arrested cells that accumulate in tissues and secrete inflammatory factors—by targeting cytomegalovirus antigens presented on HLA class II molecules. Senescent cells in human skin upregulate HLA-II and human cytomegalovirus glycoprotein B, rendering them recognizable targets for CD4+ cytotoxic killing. Another 2026 study reported that these cells expand adaptively in supercentenarians, driven by persistent exposure to tumor antigens, and may contribute to exceptional longevity through sustained cancer surveillance. Cytotoxic CD4+ T cells, in other words, can be agents of protection as well as drivers of age-associated pathology.

This duality raises important questions about the wisdom of simply depleting or suppressing these cells in older individuals. On one hand, their CCL5-mediated influence on the bone marrow clearly exacerbates myeloid bias and the pro-inflammatory microenvironment it creates. On the other, their surveillance functions—clearing senescent cells and hunting virus-infected or transformed cells—may be essential to healthy aging. The appeal of the CCL5–CCR5 intervention strategy is precisely that it does not require eliminating the cells themselves. By pharmacologically dampening the signaling conversation between cytotoxic CD4+ T cells and hematopoietic progenitors, maraviroc may dissociate the harmful hematopoietic effects of these cells from their beneficial cytotoxic functions, rebalancing the immune system while leaving its defensive capacities intact.

The study also highlights how much of immunological aging is orchestrated in the bone marrow itself rather than in peripheral tissues. The marrow is not a passive reservoir of blood cells but an active endocrine-like niche in which infiltrating lymphocytes, stromal cells and hematopoietic stem cells exchange signals that shape systemic immunity. With age, the accumulation of cytotoxic CD4+ T cells within this niche converts it into a factory for pro-inflammatory myeloid output, with downstream consequences for tissues throughout the body. Whether similar CCL5-driven mechanisms operate in other contexts of chronic T cell marrow sequestration, and whether maraviroc or related CCR5 antagonists can improve clinically meaningful outcomes such as infection resistance, vaccine responses or inflammatory disease burden in aged humans, will be the critical next steps. For now, the study offers a mechanistically precise and clinically actionable model of how the aging immune system tips toward inflammation—and a familiar drug that may help tip it back.

Subject of Research: The role of cytotoxic CD4+ T cells in driving age-associated myelopoiesis via CCL5–CCR5 signaling and its pharmacological reversal by maraviroc in aged mice.

Article Title: Cytotoxic CD4+ T cells support age-associated myelopoiesis

Article References: Cytotoxic CD4+ T cells support age-associated myelopoiesis. (2026). Nature Aging. https://doi.org/10.1038/s43587-026-01241-9

Image Credits: AI Generated

DOI: 10.1038/s43587-026-01241-9

Keywords: immunology, aging, hematopoiesis, cytotoxic CD4+ T cells, CCL5–CCR5 axis, myelopoiesis, maraviroc, bone marrow, inflammaging, Nature Aging, senescent cells, immune rejuvenation