Cytotoxic T cells infiltrate the brain and interact with microglia to reduce Alzheimer’s Disease pathogenesis

Abstract

Abstract The role of the adaptive immune system, specifically T cells, remains poorly understood in Alzheimer’s disease (AD) pathogenesis research. Our lab generated an immune-deficient mouse model of AD (RAG2ɣc−/−5xfAD) which showed a dramatic increase in amyloid plaque load, an activated microglial neuroinflammatory state, and a decrease in the ability of microglia to phagocytose beta-amyloid. Restoration of adaptive immunity via bone marrow transplantation led to a corresponding decrease in amyloid plaques, indicating a fundamental role for adaptive immunity in AD pathology. Further adoptive transfers into these aged immune-deficient mice showed a significant increase in memory CD8+ T cells and microglia in the RAG2ɣc−/−5xfAD brain parenchyma via flow cytometry. Interestingly, T cells were observed adjacent to plaque-associated microglia in these brains via Immunohistochemistry. To determine whether T cell infiltration also occurs in immune-intact AD mice, flow cytometry was conducted on 5xfAD mice that develop amyloid plaques, PS19 mice that develop neurofibrillary tangles, PS19-5xfAD bigenic mouse model, and wild-type mice. This analysis validated the immune-deficient observations, demonstrating a significant increase in memory CD8+ T cells in 5xfAD mice brains but also revealed a further significant increase in the bigenic PS19-5xfAD model. Therefore, I hypothesize that cytotoxic T cells respond to the inflammatory AD environment by infiltrating the brain and directly interacting with microglia to decrease amyloid plaques. My initial data clearly demonstrate that further examination of the crosstalk between adaptive and innate immunity is needed to determine the mechanisms by which T cells influence AD pathogenesis.