Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity, 2024, Ashkar et al

[rvallee]

Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity
Nature, open access: https://www.nature.com/articles/s41467-023-44667-0

Abstract
Although many viral infections are linked to the development of neurological disorders, the mechanism governing virus-induced neuropathology remains poorly understood, particularly when the virus is not directly neuropathic. Using a mouse model of Zika virus (ZIKV) infection, we found that the severity of neurological disease did not correlate with brain ZIKV titers, but rather with infiltration of bystander activated NKG2D+CD8+ T cells. Antibody depletion of CD8 or blockade of NKG2D prevented ZIKV-associated paralysis, suggesting that CD8+ T cells induce neurological disease independent of TCR signaling. Furthermore, spleen and brain CD8+ T cells exhibited antigen-independent cytotoxicity that correlated with NKG2D expression. Finally, viral infection and inflammation in the brain was necessary but not sufficient to induce neurological damage. We demonstrate that CD8+ T cells mediate virus-induced neuropathology via antigen-independent, NKG2D-mediated cytotoxicity, which may serve as a therapeutic target for treatment of virus-induced neurological disease.

 

[rvallee]

Bizarrely, I saw this study promoted in many places, framed this way by McMaster university it seems, as if "busting the myth" that viruses cause neurological disease, because rather it's the immune system's response. Which is really a bizarre potato-potahto since there is no infectious disease without an immune response.

 

[SNT Gatchaman]

Summary quotes from the discussion —

Despite evidence that peripheral viral infections can facilitate development of neurological disease, the contribution of viral replication and antiviral immunity to neuropathology has remained unclear. In a mouse model of ZIKV infection, our results demonstrate that while an inflammatory stimulus, such as viral infection, is necessary to induce neurological disease, the amount of infectious virus is not directly correlated with clinical symptoms. Instead, we find that ZIKV-induced neuropathology is mediated by NK cell-like bystander activated CD8 + T cells via NKG2D signaling, independent of the viral load in the CNS. Furthermore, we demonstrate that NKG2D-mediated, antigen independent killing by bystander activated T cells may promote virus-associated neurological disease.

Our data further suggest that bystander activated CD8+ T cells are recruited from the periphery by inflammatory stimuli in the brain, rather than the proliferation of brain-resident T cells. α-CD8 antibody depletion effectively depleted CD8+ T cells in the periphery, but is unable to cross the BBB and deplete brain-resident T cells. Thus, the lack of bystander activated CD8 + T cells in the brain following α-CD8 treatment suggests that these T cells are recruited from the periphery during infection.

The concept of innate-like activation of conventional CD8+ T cells, recently named bystander activation, has remained controversial since its inception. Bystander activated T cells have been proposed causes of immunopathology of viral infections but were largely ignored due to their relatively small populations or minimal activation in LCMV or non-fatal mouse hepatitis virus infection.

Despite their resemblance to NK cells, bystander activated T cells pose a significant threat during inflammatory and infectious diseases. CD8+ T cells are ‘bystander activated’ in response to hyperinflammation, most notably through IL-15 signaling. Our results suggest that IL-12/18 signaling during viral infection may also contribute to bystander activation, seen through increased CD8+ T cell NKG2D expression and antigen-independent cytotoxicity, as well as exacerbated clinical symptoms of paralysis in IL-12/18-treated ZIKV-infected mice. While NK cells possess antigen-independent activation receptors, including NKG2D, they also possess several inhibitory mechanisms to prevent off-target killing of healthy cells. In contrast, bystander activated T cells do not upregulate NK cell inhibitory receptors and are less susceptible to PD-1-mediated inhibition.