Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Central Nervous System

• Resident Memory T cells

• Neuroinflammation

Main Findings

While it has long been thought that the central nervous system (CNS) was an immune-privileged organ, this concept has recently been challenged. CNS is patrolled by T cells, responsible for protective immunity against pathogens and tumours, or following vaccination (1,2). However, T cells also participate to neuroinflammation. In this preprint (3), the authors aimed at elucidating the role of brain resident memory T cell responses following CNS injury and viral infection in mice.

Brain resident memory T cells (TRM) are characterised by the expression of CD69, together or not with CD103. The authors first showed that CD8 – but not CD4 – TRM cells accumulate in the brain of mice with age. Upon sterile neurologic injury and CNS cancers, those brain TRM rapidly expanded. To determine whether this expansion was antigen-specific, authors used a neurotropic virus, the Theiler’s Murine Encephalomyelitis Virus (TMEV), allowing the measurement of antigen-specific T cells by the use of tetramers. They showed that expansion of CD8 TRM cells following CNS viral infection was not dependent on T cell responses outside of the brain, relied on T cell proliferation, and preceded entry of viral antigen-specific T cells. More importantly, the reactivation of brain TRM induced severe neuroinflammation in the brain, measured by Magnetic resonance imaging (MRI), that was accompanied by activation and blasting of CD8 T cells, infiltration of inflammatory monocytes, and concurrent blood brain barrier permeability. The TRM reactivation paralleled a sharp decrease in circulating viral-specific T cells.

These results showed that antigen specific TRMs can induce significant neuroinflammation, neuropathology, and peripheral immune suppression. They are in line with recent work showing the importance of TRM cells in CNS protection and autoimmunity (4–6).

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Limitations

While the authors used multiple models and the results presented are extensive, the TRM cell immunophenotype remains limited, and their functionality has not been fully assessed. It may also be interesting to follow up the mechanisms leading to the expansion of non-antigen specific T cells and their fate.

To prevent the CNS egress of peripheral lymphocytes, the authors used FYT720, a sphingosine-1-phosphate receptor inhibitor, which sequesters lymphocytes in lymph nodes. Would the use of an anti-VTLA4 lead to similar results?

It would be interesting to measure whether VP2 peptides used for TRM reactivation cross the blood-brain barrier, as well as determine the impact of sterile injury on VP2-specific CD8 T cells.

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Significance/Novelty

Brain resident TRM cells are central for CNS homeostasis but are also implicated in autoimmunity. Here, the authors showed brain injury, tumour and CNS viral infection, all lead to a rapid expansion of TRM cells, independently of their specificity and preceding the increase of antigen specific TRM cells. Importantly, the reactivation of these antigen specific TRM induced neuroinflammation. The targeting of those TRM cells might thus represent an opportunity to prevent neurologic disorders.

References

1. Ellwardt, E., Walsh, J. T., Kipnis, J. & Zipp, F. Understanding the Role of T Cells in CNS Homeostasis. Trends Immunol.37, 154–165 (2016).

2. Korn, T. & Kallies, A. T cell responses in the central nervous system. Nat. Rev. Immunol. 2017 173 17, 179–194 (2017).

3. Ayasoufi, K. et al. Brain resident memory T cells rapidly expand and initiate neuroinflammatory responses following CNS injury and viral infection. bioRxiv 2022.04.08.487707 (2022) doi:10.1101/2022.04.08.487707.

4. Urban, S. L. et al. Peripherally induced brain tissue–resident memory CD8+ T cells mediate protection against CNS infection. Nat. Immunol. 2020 218 21, 938–949 (2020).

5. Vincenti, I. et al. Tissue-resident memory CD8+ T cells cooperate with CD4+ T cells to drive compartmentalized immunopathology in the CNS. Sci. Transl. Med. 14, 6058 (2022).

6. Frieser, D. et al. Tissue-resident CD8+ T cells drive compartmentalized and chronic autoimmune damage against CNS neurons. Sci. Transl. Med. 14, 6157 (2022).

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Credit

Reviewed by Nicolas Ruffin as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology  (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM).