Unlike adaptive immune memory, which is associated mainly with B cells and T cells, trained immunity describes a long-lasting functional change in innate immune cells. The innate immune system responds rapidly to threats without relying on the highly specific receptors used by adaptive immunity. After exposure to infections, vaccines, inflammatory signals or other stressors, innate immune cells and their precursors can become “trained,” responding more strongly to a later challenge. This phenomenon can improve protection against unrelated pathogens, but the new study highlights how persistent or improperly regulated training may turn into a liability over time.

The proposed connection begins in the bone marrow, where hematopoietic stem cells, or HSCs, reside in specialized microenvironments known as niches. HSCs are normally maintained in a relatively quiet state, dividing only when new blood cells are needed. During infection or tissue injury, inflammatory cytokines and other danger signals can activate these cells and redirect blood production toward myeloid cells, including monocytes, macrophages and neutrophils. This emergency response is useful in the short term. However, repeated or prolonged exposure to inflammatory signals may leave a durable imprint on HSCs, changing how they behave even after the original threat has disappeared.

That imprint can involve several layers of cellular regulation. Inflammatory stimulation may alter chromatin, the DNA-protein structure that controls access to genes, as well as DNA methylation, metabolic pathways and the activity of transcription factors. These changes can influence which genes are switched on when an HSC produces descendants. A stem cell affected by trained immunity may therefore generate blood cells with an enhanced tendency to produce inflammatory mediators. Over years, this could create a self-reinforcing system in which inflammation modifies stem cells, and the altered stem cells continually replenish inflammatory immune populations.

This mechanism offers a framework for understanding why aging is accompanied by a gradual shift in blood-cell production. With advancing age, HSC populations often become more heterogeneous and may favor myeloid output over the generation of lymphoid cells. The result can be a larger supply of innate immune cells alongside a weaker capacity to produce certain lymphocytes, contributing to an immune system that is simultaneously more inflammatory and less adaptable. The authors’ concept of maladaptive trained immunity places this imbalance upstream, suggesting that long-term changes in stem-cell behavior may help organize the broader immune dysfunction seen in older adults.

The idea also overlaps with research into clonal hematopoiesis, a process in which genetically or epigenetically altered HSCs expand and produce a substantial fraction of a person’s blood cells. Some of these clones carry mutations in genes involved in epigenetic control or inflammatory signaling. Their descendants can release elevated levels of cytokines such as interleukin-1 beta and interleukin-6, molecules that help coordinate immune responses but can damage tissues when persistently produced. Trained immunity and clonal hematopoiesis are not identical, yet both illustrate how long-lived changes in HSCs can influence the inflammatory state of the entire body.

The proposed model may help explain why inflammation can persist without a continuing infection. In younger individuals, inflammatory responses are generally followed by resolution, a coordinated process involving anti-inflammatory signals, tissue repair and the removal of activated cells. Aging can weaken these resolution pathways while increasing exposure to inflammatory stimuli from damaged tissues, altered gut microbes, metabolic stress and recurrent infections. If HSCs retain a memory of these pressures, the bone marrow may continue producing immune cells primed for aggressive responses. The immune system would then remain prepared for danger, but at the cost of damaging healthy tissues.

The implications extend beyond basic immunology. If maladaptive trained immunity is a major driver of inflammaging, interventions might need to target the bone marrow and HSC regulatory networks rather than suppress inflammation throughout the body. Possible strategies could include selectively interrupting inflammatory cytokine signaling, restoring metabolic or epigenetic balance in HSCs, improving the bone-marrow niche, or reducing the expansion of harmful blood-cell clones. Such approaches would require caution because completely blocking trained immunity could impair protection against infection and weaken beneficial vaccine responses. The challenge would be to distinguish protective immune memory from the persistent, pathological form described by the authors.

The study also points toward new ways of studying biological age. Blood-cell composition, inflammatory proteins, HSC activity and epigenetic signatures could potentially be combined to identify people whose immune systems have entered a maladaptive state. Future research will need to determine how permanent trained-immunity signals are, whether they can be reversed, and which exposures are most important in establishing them. By placing hematopoietic stem cells at the center of the inflammaging process, Divangahi and King provide a unifying hypothesis: the aging immune system may not simply become weaker, but may be actively reprogrammed by its history of inflammatory encounters. Understanding that history could become essential to slowing age-related disease while preserving the immune system’s ability to respond when real threats arrive.

Subject of Research: Hematopoietic stem cells, trained immunity, inflammaging and age-related immune dysfunction

Article Title: Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging

Article References: Divangahi, M., King, K.Y. Maladaptive trained immunity as a hematopoietic stem cell driver of inflammaging. Nat Aging (2026). https://doi.org/10.1038/s43587-026-01197-w

Image Credits: AI Generated

DOI: 10.1038/s43587-026-01197-w

Keywords: trained immunity, hematopoietic stem cells, inflammaging, aging, innate immunity, bone marrow, clonal hematopoiesis, inflammation, immune memory, cytokines

Tissue-resident memory T cells serve as frontline sentinels to swiftly identify and respond to viral pathogens in barrier tissues such as the lungs. Traditionally, TRM cells were thought to be strictly localized, maintaining protection at the site of initial infection without migrating to distant lymphoid tissues. However, the current study challenges this dogma by demonstrating that lung TRM cells can migrate retrogradely—that is, from the lung back to the lung-draining lymph nodes (dLN)—thereby creating a reservoir that sustains immune vigilance beyond the infected tissue.

Using an array of sophisticated single-cell tracking methodologies in murine models infected with influenza A virus (IAV), the researchers tracked lung TRM cells over time. These techniques allowed for precise lineage tracing and gene expression profiling of individual T cells, providing unprecedented resolution of their migratory patterns and functional states. Remarkably, the molecular signatures of TRM cells found in the lung-draining lymph nodes closely matched those derived from the lung tissue, indicative of retrograde migration rather than independent local differentiation.

At the molecular level, the chemokine receptor CCR5 emerged as a pivotal factor orchestrating this trafficking. CCR5 interacts with its ligand, CCL5, to guide the movement of TRM cells from the lung environment toward the lymph nodes. Functional blockade experiments using the CCR5 antagonist Maraviroc resulted in a pronounced reduction of TRM cells in the draining lymph nodes, confirming the receptor’s role in this directional migration. Importantly, CCR5 inhibition did not affect TRM cell numbers within the lungs, isolating the receptor’s effect to the lung-to-lymph node migratory axis.

Inside the draining lymph nodes, TRM cells exhibit reduced apoptotic rates compared to their counterparts in lung tissue, suggesting these lymphoid niches provide survival signals that maintain a stable memory pool. The crosstalk between lung and lymph node TRM cells forms a dynamic maintenance loop: lung-derived TRM cells retrograde migrate and persist in the dLN with preserved transcriptional identity, while upon secondary viral challenge, these dLN-resident TRM cells can re-enter the lung tissue and differentiate back into resident memory cells, reinforcing localized immunity.

This novel loop of retrograde migration and repercussion is of critical importance, especially in the context of recurrent infections such as influenza where rapid reactivation of protective immunity can substantially minimize disease severity. It signifies that antiviral memory is not confined to a single tissue compartment but is actively managed through inter-organ cellular traffic that balances frontline defense with the preservation of long-term memory.

Furthermore, the implications of these findings extend to vaccine development strategies. Traditional vaccination approaches primarily target systemic immunity, often neglecting the tissue-resident lymphocyte populations crucial for prompt local response. By understanding the molecular underpinnings and maintenance dynamics of TRM cells, especially the CCR5-driven migratory circuit, next-generation vaccines can be designed to strategically harness or amplify this pathway, leading to more durable and potent immunity in mucosal tissues like the lungs.

The study also opens exciting avenues for therapeutic intervention. Considering that CCR5 is already a druggable target—with existing FDA-approved antagonists used in other disease contexts such as HIV infection—pharmacological modulation of this pathway could enhance or dampen tissue-specific immunity as clinically warranted. This could be particularly beneficial in respiratory diseases where excessive inflammation or inadequate immune surveillance plays a role.

Importantly, the researchers emphasize that the preservation of TRM cells through retrograde migration does not compromise their effector functions. Single-cell transcriptomic analyses revealed that these cells retain their capacity for rapid cytokine production and cytotoxic activity, even after relocation and persistence within lymph nodes. This retention of functional competency underscores the evolutionary advantage of this bidirectional migration loop: sustained readiness without functional exhaustion.

From a broader immunological perspective, these findings challenge the long-held notion that memory T cells in peripheral tissues exist in isolation. Instead, they reveal complex, physiologically relevant migratory networks that ensure systemic coordination and maintenance of immune memory. Such mechanisms likely apply beyond the lungs to other mucosal and barrier tissues, suggesting a universal principle of tissue immunity.

Corresponding author Hai Qi stated, “Our study reveals a highly dynamic yet finely tuned maintenance loop between the lung and its draining lymph nodes. This extends the conceptual framework of tissue-resident immunity and offers concrete molecular targets to enhance long-term protection, particularly against respiratory viruses. Future work will assess whether similar circuits exist in human tissues and how they can be leveraged clinically.”

Institutions such as Tsinghua University, a global leader in scientific innovation, and the biomedical-focused Changping Laboratory have contributed significantly to this advancement by integrating cutting-edge immunological tools with translational research perspectives. Their collaborative approach underscores the importance of interdisciplinary methods in unraveling complex immune dynamics.

As respiratory pathogens continue to challenge public health worldwide, particularly amid recurring pandemics, insights into the persistence and mobilization of TRM cells provide a promising foothold for novel interventions. This study not only enriches fundamental immunology but also inspires hope for improved clinical outcomes through vaccine refinement and novel immunomodulatory approaches.

In summary, this research offers compelling evidence that lung tissue-resident memory T cells do not function in permanent isolation but engage in a regulated migratory circuit facilitated by the CCR5–CCL5 axis. By migrating retrogradely to the lymph nodes and maintaining viability and identity there, these cells contribute to a robust and adaptable immune memory system poised to defend the respiratory tract upon reinfection. Such findings redefine our understanding of immune memory compartmentalization and open a new frontier in respiratory immunology.

Subject of Research: Tissue-resident memory T cell dynamics in lung and lymph node interaction post-influenza infection.

Article Title: Not provided.

News Publication Date: Not provided.

Web References: http://dx.doi.org/10.1007/s11427-024-2920-y

References: Not provided.

Image Credits: ©Science China Press

Keywords: tissue-resident memory T cells, TRM, retrograde migration, CCR5, CCL5, influenza A virus, lung immunity, lymph nodes, immune memory maintenance, Maraviroc, respiratory tract immunity