Modulating T cell inflammation in a mouse model of Alzheimer’s disease

Abstract

AbstractBackgroundRecent single cell transcriptomic studies using peripheral blood and post‐mortem brain samples from Alzheimer’s disease (AD) patients have suggested a significant role for T cells in modulating AD‐related neuroinflammation. Previous findings from our group and others show that T cells in AD patients and aged individuals are clonally expanded and upregulate genes related to inflammation, cytotoxicity, and senescence. We have found that TSC22D3, a putative anti‐inflammatory transcription factor, is upregulated in brain‐infiltrating CD8+ T cells and found in gene co‐expression modules in peripheral blood from AD patients.MethodWe are pursuing the mechanism of TSC22D3 function and its effect on T cell biology and AD neuropathology. We have generated mice that lack TSC22D3 in CD8 T cells on the 5XFAD background, a mouse model of AD. We used flow cytometry to measure populations of various immune cell subtypes, and sort T cell subtypes for downstream sequencing. We are also using immunocytochemistry to quantify markers of amyloid and tau pathology, microglial interaction with amyloid plaque, and neuronal and synaptic loss in the hippocampus. Finally, we are examining the induction of immune reactions to amyloid and tau protein in TSC22D3 conditional knockout mice without AD transgenes.ResultIn human tissue, TSC22D3 is highly expressed in brain‐infiltrating CD8+ T cells along with genes associated with a senescent, late‐differentiation phenotype. Flow cytometry analysis showed that late‐stage AD mouse splenocytes bore significantly higher percentages of dendritic cells and various cytokines in CD4+ T cells than non‐AD or younger AD mice. Most of these differences were independent of TSC22D3 conditional knockout status. Ongoing bulk sequencing may reveal TSC22D3‐dependent changes in T cell gene expression, with effects on key markers of AD progression in the hippocampus.ConclusionTSC22D3 is known to directly suppress NFkB and other pro‐inflammatory mediators. Its co‐expression with more pro‐inflammatory and cytotoxic genes in brain‐infiltrating CD8+ T cells may represent a compensatory mechanism in the face of neuroinflammation related to aging and AD. We expect that knockout of TSC22D3 in CD8+ T cells will increase expression of pro‐inflammatory genes in T cell subsets, and will manifest in advanced AD pathology in older adult mice.