When Brain Defenders Turn Destructive: How Microglia and T Cells Promote Age-Related Decline

A recent study by Janos Groh and colleagues in Mikael Simons’ lab at the Institute of Neuronal Cell Biology, Technical University of Munich, explores how immune responses contribute to white matter degeneration during aging. Published in Nature Neuroscience, the work investigates the role of activated microglia in driving neuroinflammation and identifies a harmful cascade involving cytotoxic CD8⁺ T cells. Central to this process is the CXCL10–CXCR3 signaling pathway. These findings define a molecular pathway that may underlie chronic immune activation in age-associated white matter degeneration.

Microglial Dysfunction in Aging White Matter

White matter in the aging brain is especially vulnerable to damage. White matter refers to regions in the brain and spinal cord that are primarily composed of nerve fibers (axons) that are coated in myelin, which gives it the characteristic white appearance. Myelin sheaths are formed by oligodendrocytes and gradually accumulate reactive oxygen species in old age, leading to structural alterations such as decompaction, fragmentation, and eventual axonal disruption. These changes correlate with reduced integrity of the nerve fiber tracts and consequently cognitive decline in older individuals.

As is often the case in degenerative conditions, some aspects of its progression can be attributed to an inappropriate reaction of the immune system – be it an insufficient, excessive, or misdirected reaction. In this case, the crucial players involved are microglial cells and T cells of the CD8+ subtype.

Microglia are the CNS-resident macrophages, and they normally play a central role in maintaining white matter integrity by clearing damaged myelin. However, in aging, this system becomes overwhelmed, and the phagocytic capacity of microglia cannot keep up with progressive myelin breakdown. As a result, chronic neuroinflammation emerges, where persistent myelin aberrations trigger a shift in microglial state. They adopt transcriptional profiles reminiscent of disease-associated microglia, also known as “reactive microglia”, characterized by enhanced pro-inflammatory signaling, lysosomal content, lipofuscin-filled vesicles, and distinctive pathological changes including cytoplasmic spheroids and beading.

Importantly, these reactive microglia are often found in conjunction with a special type of T-cells in aged or diseased CNS tissue, the CD8⁺ T cells. Rather than mitigating pathology, CD8⁺ T cells appear to worsen it, promoting axon loss and oligodendrocyte damage. This consistent association raises the question of how reactive microglia and CD8⁺ T cells interact in white matter compartments.

Modeling Dysregulated Microglial Activation in the aged Optic Nerve

To probe this relationship, the researchers selected the optic nerve as their model system. Its anatomical features and the ability to assess optic nerve damage behaviorally – via visual acuity testing with Striatech’s OptoDrum – make it a well-suited proxy for aging white matter.

Two distinct models of microglial disturbance in aging were used in this study, both causing a higher relative population of reactive microglia. In the first model, the researchers triggered an increased activation of microglia by pharmacological treatment with PLX5622, an agent that targets microglial survival pathways, induces depletion of CSF1R-dependent microglia and thus a preferential reduction in homeostatic microglial populations. The second model, a genetic model, utilized CX3CR1-deficient mice. CX3CR1 is a chemokine receptor associated with neuroprotective, anti-inflammatory microglial phenotypes, and its deletion results in a propensity for pro-inflammatory activation of microglial cells.

Both approaches resulted in an increased frequency of CD11c expressing microglia in aged optic nerves. CD11c is a marker that can be used to identify a transition of microglia to activated states. Electron microscopy revealed common pathological features, including fragmented myelin, axonal spheroids, and accumulation of cellular debris. In PLX5622-treated animals, microglia contained intracellular myelin remnants and enlarged lysosomal inclusions, suggesting ongoing but inefficient clearance of myelin debris. In contrast, CX3CR1-deficient microglia contacted abnormal myelin but failed to phagocytose it.

These structural changes in the optic nerve were accompanied by inner retinal thinning, a loss of retinal ganglion cells (RGCs), and significantly reduced visual acuity in both models, as measured with Striatech’s OptoDrum system.

Measurements with Striatech’s OptoDrum show that visual acuity is significantly reduced in aged mice in both experimental models.

Reproduced from Figure 2 of the original publication under the Creative Commons Attribution (CC BY 4.0) license.

Microglial Heterogeneity Revealed by Single-cell RNA Sequencing

The researchers performed single-cell RNA sequencing (RNA-seq) of microglia in to dissect the transcriptional changes underlying these observations. Three microglial clusters emerged in aged white matter. The first cluster showed increased expression of canonical inflammatory genes, while the second cluster was enriched for phagocytosis-related transcripts, oxidative phosphorylation, and ribosomal genes. The third cluster of microglial cells, enriched in aged PLX5622-treated animals, exhibited a hybrid profile that combined elevated inflammatory markers with genes related to antigen presentation and T cell interaction.

In parallel, other glial cells exhibited stress-related adaptations. Oligodendrocytes (responsible for the myelin sheath) showed upregulation of DNA damage response genes and markers of protein stress. Astrocytes adopted reactive transcriptional signatures, indicated by increased GFAP expression. Together, these results indicate that microglial dysregulation advances broader glial network disturbances.

CD8+ T Cells Drive White Matter Destruction in Aging

Both approaches targeting microglial function in aged white matter showed striking accumulation of CD8⁺ T cells near CD11c-positive microglia. These T cells displayed features of tissue-resident memory (TRM) cells, including expression of granzyme B, suggesting cytotoxic capabilities. Furthermore, CD8⁺ T cells spatially colocalized with axonal spheroids and reactive oligodendrocytes, raising the possibility that they actively contribute to tissue injury.

To test this, the authors generated aged CD8-deficient mice, which lack functional CD8⁺ T cells, and subjected them to PLX5622 treatment. This approach isolated the effects of microglial depletion from T cell involvement. While myelin abnormalities and microglial CD11c expression remained, key markers of neurodegeneration, like axonal spheroids, loss of retinal ganglion cells, and retinal thinning, were significantly reduced. Visual acuity, assessed by Striatech’s Optodrum, was also markedly improved compared to CD8-sufficient counterparts. These findings confirm a causal role for CD8⁺ T cells in exacerbating glia-induced white matter degeneration.

The visual acuity of aged CD8-deficient mice was less affected by PLX5622 treatment.

Reproduced from Figure 5 of the original publication under the Creative Commons Attribution (CC BY 4.0) license.

The CXCL10–CXCR3 Axis Links Glial Activation to T Cell Recruitment

To understand the molecular signals driving CD8⁺ T cell recruitment, spatial transcriptomics using MERFISH (Multiplexed Error-Robust Fluorescence In Situ Hybridization) was employed. This method allows for the simultaneous mapping of over 500 mRNAs with single-cell resolution, while retaining spatial information.

MERFISH analysis revealed reduced overall microglial numbers following PLX5622 treatment, consistent with partial depletion, alongside increased T cell infiltration. A particular chemokine, CXCL10, was expressed across multiple glial cell types, including astrocytes, and microglia (Chemokines are small signal proteins playing an important role in immune response, by guiding immune cells toward regions of high chemokine expression, usually regions with tissue damage). CD8⁺ T cells were spatially associated with the cells expressing CXCL10, supporting CXCL10’s role as a chemotactic cue. Gene expression profiling of the T cells confirmed robust expression of the cognate receptor CXCR3 for the CXCL10 chemokine.

This data led the authors to propose a three-component model: (1) CD11c-positive microglia initiate an inflammatory response, (2) reactive astrocytes and microglia upregulate expression of the chemokine CXCL10, thereby amplifying the reactive microglia signal, and (3) CXCR3-positive CD8⁺ T cells are recruited to the site and mediate cytotoxic damage.

Genetic Validation of the Ligand-Receptor Pathway

To test this model, sophisticated transgenic mouse models were studied. Trem2-deficient mice, whose microglia remain locked in homeostatic, non-reactive states, were used to determine whether microglial reactivity is required for CXCL10 upregulation and T cell infiltration. These animals showed reduced CD11c expression, less CXCL10, and lower CD8⁺ T cell density, despite increased levels of myelin disruption.

In a subsequent inquiry, aged CXCL10-deficient mice were analyzed. These mice had comparable myelin damage and microglial activation to controls; nevertheless, these animals exhibited a substantial reduction in CD8⁺ T cell infiltration, fewer axonal spheroids, less loss of retinal ganglion cells, und unaffected visual acuity. This confirmed the necessity of the chemokine CXCL10 for T cell recruitment and persistence.

CXCL10-deficient mice do not experience age-dependent visual decline.

Reproduced from Figure 7 of the original publication under the Creative Commons Attribution (CC BY 4.0) license.

To assess the role of the chemokine receptor CXCR3 on T cells, Rag1^—/— mice lacking adaptive immunity were reconstituted with either wild-type or CXCR3-deficient bone marrow. Only animals receiving wild-type (CXCR3-competent) cells developed significant T cell infiltration, axonal damage, and CD8⁺ T cell persistence in the CNS.

Implications for Aging White Matter

This study identifies the CXCL10–CXCR3 axis as a mechanistic link between microglial dysfunction and CD8⁺ T cell-driven neurodegeneration in the aging CNS. The findings suggest that CD8⁺ T cells become misdirected by glial signals and contribute to a cycle of persistent inflammation and axonal injury.

Unlike traditional immune responses aimed at pathogens, this glia–T cell crosstalk appears to be maladaptive in the aging brain. The activated glia may present myelin-derived age-associated antigens, propagating T cell engagement and tissue damage.

Targeting this pathway, either by modulating microglial activation, blocking CXCL10 or CXCR3, or interfering with T cell persistence, may represent a promising strategy for preserving white matter integrity and cognitive function during aging.

Blog author: Emilia Kawecka, Technical University of Munich, Student Assistant at Striatech

Original article: Groh, J., Feng, R., Yuan, X. et al. Microglia activation orchestrates CXCL10 mediated CD8+ T cell recruitment to promote aging-related white matter degeneration. Nat Neurosci 28, 1160–1173 (2025). https://doi.org/10.1038/s41593-025-01955-w