Immune cells are regarded as the body’s antiviral guardians. But some infections by pathogens such as Zika virus (ZIKV) can bring out the ‘dark side’ of CD8+ T cells. In these cases, T cells can also play a pathogenic role, highlighting the complex balance between immunity and inflammation.
Prior reports focused on the dual role of CD8+ T cells in the central nervous system. Lisa Ng, the Executive Director and a Senior Principal Investigator at A*STAR Infectious Diseases Labs (ID Labs) said that a key characteristic of the ZIKV resurgence in 2015 was its preference for neural cells; evidence suggested a correlation with neurological disorders in adults and birth defects in infants.
Ng teamed up with researchers from A*STAR’s Singapore Immunology Network (SIgN) and Institute of Molecular and Cell Biology (IMCB) to study the lesser-known effects that CD8+ T cells might have on non-neural tissues such as the skin. The group hypothesised that CD8+ T cells may have a long-term pathogenic effect on the skin in the aftermath of ZIKV infections, especially in the absence of CD4+ T cells.
To test the theory, the researchers developed a genetically engineered, T-cell-deficient mouse model known as TCR knockouts (TCRKO).
Activated CD8+ T cells, transferred from ZIKV-experienced mice into TCRKO mice, effectively diminished viral loads, achieving clearance within 40 days post-infection. Significant eye and ear tissue damage was also observed in mice receiving activated CD8+ T cells, unlike in wildtype and control animals.
The researchers hypothesised that in the absence of regulatory input from other T cell types like CD4+, ZIKV-primed CD8+ T cells can become self-reactive, mistakenly targeting the body's own tissues. Single-cell RNA sequencing data underpinned this hypothesis, revealing a heightened proinflammatory profile in the CD8+ T cells.
“Our findings indicate the importance of monitoring chronic skin diseases in patients previously exposed to ZIKV, as they may harbour ZIKV-specific or autoreactive memory CD8+ T cells capable of triggering skin conditions,” Ng said.
The team is currently working on identifying and understanding the specific interactions between T cells and ZIKV antigens that result in skin pathologies.
Ng explained that this finding could significantly influence vaccine development, emphasising the need to design vaccines that do not activate T-cell responses against these viral antigens.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Infectious Diseases Labs (ID Labs), the Singapore Immunology Network (SIgN) and the Institute of Molecular and Cell Biology (IMCB).
