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Radiation-induced brain injury (RIBI) is the most common complication of cranial radiation therapy in patients with head and neck cancer.
Radiation exposure can cause acute adverse effects such as headache and drowsiness, as well as delayed brain injury, characterized by brain necrosis and cognitive impairment over 3 to 5 years, which can gradually progress to uncontrolled herniation and death
.
The damaging effects of T cells have been found
in autoimmune diseases and aging.
Innate immune responses mediated by glial cell activation and subsequent neuroinflammation may be involved in the development
of RIBI.
through the chemokine CCL2/CCL8.
The researchers found that the number of T lymphocytes (CD8 positive), microglia and monocyte-phagocytes increased in the brain tissues of 2 RIBI patients, while the number of oligodendrocytes, oligodendrocytes precursor cells, and endothelial cells was significantly reduced
.
Single-cell sequencing experiments found that the expression of the genes PRF1 and granzyme A encoding perforation protein in the brain tissues of RIBI patients was elevated
.
In addition, immunofluorescence experiments found significant neuronal death in the patient's brain tissue, with CD8-positive T lymphocytes close to these apoptostic neurons
.
Figure 1: Clearing CD8-positive T lymphocytes alleviates symptoms in RIBI model mice
Infiltration of CD8-positive T lymphocytes was also clearly observed in γradiation-induced RIBI animal models.
Reduction of CD8-positive T lymphocytes significantly alleviated nerve loss in RIBI model mice.
Further ligand-receptor interactions were found to have the closest
interaction between microglia and CD8-positive T lymphocytes.
Spatially located microglia are also close to CD8-positive T lymphocytes
.
Single-cell sequencing technology showed that the number of pro-inflammatory microglia expressing the chemokines CCL2, CCL8, CCL3 and CCL4 increased, and the expression of CCL2 and CCL8 in the brain tissues of RIBI patients was increased
.
CD8-positive T lymphocytes express receptors CCR2, CCR5
.
In vivo cell experiments have found that activated CD8-positive T lymphocytes migrate around microglia exposed to radiation, significantly inhibiting this migration
by inhibiting the CCL2-CCR2 or CCL8-CCR5 signaling pathways.
The specific knockout of microglia Ccl2 or CCL8 by genetic tools in mice can significantly slow down brain damage caused by γ rays and attenuate the infiltration
of CD8-positive T lymphocytes.
After neutralizing antibodies inhibit the activity of CCR2 and CCR5, it can also significantly slow down the apoptosis of neurons caused by γ radiation and weaken the infiltration
of T lymphocytes.
Figure 2: Microglia-derived CCL2 and CCL8 regulate CD8-positive T lymphocyte infiltration
CD3 and CD8-positive T lymphocytes were found to infiltrate ischemic tissue, and these infiltrated T cells Ccr2 and Ccr5were found in the surgical resection tissue of 5 stroke patients.
Similar T cell infiltration can also be observed in animal models of stroke, and microglia co-express CCL2 and CCL8, which can reduce T cell infiltration and reduce the volume of brain damage after inhibiting CCL2 and CCL8 activity
.
These results suggest that microglia-derived CCL2 and CCL8 signaling regulates CD8-positive T lymphocyte infiltration into stroke-damaged tissues
.
In this review, inflammatory T cell infiltration in brain tissue caused by radiotherapy was found to be through clinical tissue samples, which can cause neuronal death
.
Furthermore, single-cell sequencing found that there was a strong interaction between CCL2 and CCL8 secreted by microglia and Ccr2 and Ccr5 expressed on T cells, which could alleviate neuronal death
after inhibiting the above chemokine signaling.
【References】
Shi et al.
, Microglia drive transient insult-induced brain injury by chemotactic recruitment of CD8+ T lymphocytes,Neuron (2022),
https://doi.
org/10.
1016/j.
neuron.
2022.
12.
009
The images in the article are from references
