CD8+ tissue-resident T-cell regulation of microglia function

Our primary aim is to uncover the factors that determine whether microglial activation resolves or progresses into chronic inflammation. To achieve this, we need to identify the ligands and receptors involved in regulating microglial responses. Our previous research has indicated that CD8+ tissue-resident memory T (TRM) cells may play a crucial role in driving chronic inflammation in the brain. These CD8+ TRM cells function as sentinels in tissues, quickly alerting their surroundings upon encountering an antigen, providing rapid local defense during reinfections. While essential for protection against local reinfections, these cells can become detrimental in certain diseases by contributing to localized pathology.

The central objective of this proposal is to explore how microglia are activated within the CD8+ TRM niche and assess the implications for disease progression. Using a well-established model of early-life virally induced brain infection in mice, we will generate persistent focal areas of CD8+ TRM cell accumulation. We will investigate the timing and location of microglial activation within this niche, and conduct a focused screen using CD8+ T cell transfer to systematically identify effector molecules and their effects on microglia. Additionally, we will test the hypothesis that interferon-responsive microglia within the CD8+ TRM niche may serve as hotspots for age-related white matter damage and amyloid plaque formation. This proposal seeks to establish a novel link between prior viral infections, CD8+ TRM cells, microglial activation, and their potential contributions to aging and Alzheimer’s disease.