Professor Tang Yamei's team at Sun Yat-sen University discovered a novel mechanism by which microglia infiltrate the brain parenchyma through chemotaxis peripheral CD8⁺ T cells Cell Press Dialogue Scientists

Life Sciences

Life science

On January 5, 2023, Professor Tang Yamei's team from the Brain Science Research Center of Sun Yat-sen Memorial Hospital of Sun Yat-sen University published a report entitled "Microglia drive transient insult-induced brain injury by chemotactic recruitment of CD8⁺" in the journal Neuron of Cell Press Cell Press T lymphocytes" research paper elucidates the mechanism by which microglia secrete chemokines CCL2 and CCL8 after radiation attract CD8⁺ T cells to infiltrate brain tissue and cause brain injury, and propose new intervention strategies
for the treatment of radiation brain injury 。 The study was completed with the support of the National Natural Science Foundation of China Outstanding Youth Program and Key International Cooperation Project, with Shi Zhongshan and Yu Pei, postdoctoral fellows of the Department of Neurology, Sun Yat-sen Memorial Hospital Sun Yat-sen University, Lin Weijie, associate researcher and research assistant Chen Sitai as the co-first author of the paper, and Professor Tang Yamei as the only corresponding author
of the paper.
The study was also supported
by Professor Long-Jun Wu of the Mayo Clinic and Professor Ho Ko of the University of Chinese Hong Kong.

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Radiation-induced brain injury (RIBI) is a serious complication of head and neck tumor after radiotherapy, mostly 3-5 years after the end of radiotherapy, clinical manifestations are cognitive impairment or epilepsy and other symptoms, pathological changes are brain tissue edema, necrosis, etc.
, seriously affecting the quality of life of
patients.
At present, the pathogenesis of radiation brain injury is unclear and the treatment methods are limited, making the clinical prevention and treatment of radiation brain injury one of
the key problems in the field.

In recent years, in Alzheimer's disease, Parkinson's disease and other neurological diseases, the infiltration of cerebrospinal fluid and brain tissue, an important participant of acquired immunity, by T lymphocytes into cerebrospinal fluid and brain tissues has been discovered, but the mechanism and possible pathogenic mechanism of T lymphocyte infiltration into the central nervous system still need to be elucidated
.
In this study, in order to systematically study the cell types and molecular mechanisms involved in radiation brain injury, the authors first performed single-cell transcriptome sequencing analysis on tissue samples obtained during resection of radiation brain injury lesions, and found that there was significant CD8⁺ T cell infiltration in the lesions
.
At the same time, single-cell TCR sequencing results for different patient lesions also showed that CD8⁺ T cells infiltrating brain tissue underwent significant clonal expansion
.
Multiple evidence suggests that infiltrated CD8+ T cells may cause brain tissue damage, and the authors prepared a radioactive brain injury model in CD8a-DTR transgenic mice and wild-type mice based on the previous research results of the research group (He, et al, FASEB journal, 2020), and systematically knocked out systemic CD8+ T cells using diphtheria toxin or Cd8a neutralizing antibody, respectively, and found CD8⁺ The brain injury lesions were significantly reduced after T cell knockout, confirming that CD8⁺ T cells play a key role
in mediating the occurrence of radiation brain injury.

Next, the authors further explored
the mechanism of how CD8⁺ T cells infiltrate brain tissue after radiation.
Through cell interaction analysis, it was found that a group of microglia subsets with high expression of chemokines such as CCL2 and CCL8 may trigger the chemotaxis of CD8⁺ T cells into the brain
.
Using RNAscope staining, in vitro experiments, microglia-specific knockout of CCL2 or CCL8 transgenic mouse models, neutralizing antibodies and small molecule inhibitors, the authors demonstrated that intervention in the CCL2/CCL8-CCR2/CCR5 signaling pathway can effectively inhibit CD8⁺ T cell migration and significantly reduce the focus
of radiation brain injury.

In other neurological diseases such as cerebral ischemia, there has also been a literature report of infiltration of peripheral CD8⁺ T cells into the central nervous system
.
Therefore, the research team further explored whether the above CCL2/CCL8-CCR2/CCR5 signaling pathway is also involved in other brain diseases, and finally determined that blocking this signaling pathway can significantly reduce brain damage
caused by middle cerebral artery ischemia (MCAO).

This study is the first to prove that after the brain is stimulated by radiation or cerebral ischemia, microglia secrete chemokines CCL2 and CCL8, attract peripheral CD8⁺ T cell infiltration, and release cytotoxic factors such as perforin and granzyme, causing secondary damage
to the brain.
At the same time, this paper also provides an innovative theoretical and experimental basis
for the prevention and treatment of brain diseases such as radiation brain injury and cerebral ischemia by inhibiting T lymphocyte-mediated acquired immunity.

Overview of the full-text research mechanism

Author's interview

Cell Press specially invited Professor Tang Yamei to accept an exclusive interview on behalf of the research team.

Ask her to explain
it in more detail for you.

CellPress：

What are the characteristics of radiation brain injury diseases?

Professor Tang Yamei:

Radiation brain injury is more common after radiotherapy for head and neck tumors, especially in areas with high incidence of nasopharyngeal cancer, such as in South China and Southeast Asia, very common, the main feature of radiotherapy brain injury is delayed and progressive aggravation, it is generally found 3-5 years after the end of radiotherapy, and will continue to aggravate
.
The pathogenesis of radiation brain injury is very complex, involving many links, and it is necessary to explore and study step by step, and then find new intervention targets
.
Our study shows that CD8⁺ T cells associated with acquired immunity play an important role in the pathogenesis of radioactivity, and also confirms the complexity of the pathogenesis of
radiation brain injury.

CellPress：

The brain is often considered an immune immune organ, so why did you choose to start with immunity to explain the mechanism of radiation brain injury?

Professor Tang Yamei:

The brain is inevitably damaged by radiation in the radiation therapy of head and neck tumors, some patients present with acute injury, symptoms are repaired in a short time, most patients present with delayed radiation brain injury, and the symptoms of patients appear 3-5 years after the end of radiotherapy, mainly manifested as cognitive impairment and other symptoms, indicating the presence of chronic nerve damage characteristics
.
In recent years, studies in diseases such as multiple sclerosis and Alzheimer's disease have found that peripheral infiltrating T cells and disease-associated microglia may be involved in the occurrence and development of chronic neurological diseases, which has inspired us
.
In addition, based on unsupervised clustering and cell interaction analysis at the single-cell level, we determined that there is significant microglial inflammation and cytotoxic T cell chemotaxis infiltration mechanisms in the brain, thereby firmly studying the mechanism
of radiation brain injury from the perspective of acquired immunity.

CellPress：

What is the potential clinical value of the study?

Professor Tang Yamei:

In addition to workers in the aerospace field and nuclear industry, patients with radiation brain injury are generally tumor patients in the early stage, and for tumor treatment, CD8+ T tumor immunity is required, but if CD8+ T cells enter normal brain tissue, it will cause brain damage, so one aspect of the clinical value of this study is to reduce CD8⁺ T cells provide a reference for brain tissue infiltration, which is a new direction
for the treatment of radiation brain injury.
More importantly, our study confirms that microglia infiltrate the brain parenchyma through the CCL2/CCL8-CCR2/CCR5 signaling pathway chemotaxis CD8⁺ T lymphocytes in the ischemic brain injury model are also involved in the occurrence and development of diseases, based on the common mechanism, our research provides inspiration and reference for the development of new treatments for other neurological diseases, including stroke
。

CellPress：

What are the team's future research plans in the direction of radiation brain injury or neuroimmunity?

Professor Tang Yamei:

Due to the complexity of the pathogenesis of radiation brain injury, we currently only have a partial understanding of its full picture, in the future, we will continue to study the various links involved in radiation brain injury, various cells and molecules, and strive to understand the mechanism more comprehensively and truthfully, and then target key links and key molecules to try new treatments.

We are interested in the participation of neuroimmunity in the occurrence of many neurological diseases, which have both similarities and differences, and then the research group will continue to deeply analyze the role of neuroimmunity in neurodegenerative diseases, and provide a new direction
for the treatment of brain diseases.