Fight Aging!

The immune systems of the body and brain are distinct and separate, or at least largely separate, influencing one another via signaling. The blood-brain barrier keeps the vast majority of immune cells in the body out of the brain, and vice versa. A few channels have been discovered in recent years whereby a small number of adaptive immune cells, such as T cells, enter the brain in the normal course of events. Additionally, the blood-brain barrier becomes dysfunctional and leaky with age, allowing a wide range of unwanted cells into the brain, T cells included.

Increasing inflammatory activity in the innate immune cells of the brain known as microglia is a growing focus of research interest in the context of aging and neurodegenerative conditions. While some of of this maladaptive behavior arises from reactions to local conditions and internal age-related damage, some is driven by interactions with the body's immune system. Along the way, attention has also turned to the entry of T cells into the brain, and their potential role in provoking inflammatory neurodegeneration. In today's open access paper, for example, researchers demonstrate that dendritic cells encourage T cells to enter the brain to cause problems. Removing the dendritic cells in mice reduces the impact of T cells on the aging of the brain and progression of neurodegeneration.

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration

Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease and certain forms of frontotemporal dementia, defined by the intracellular aggregation of hyperphosphorylated tau protein, which tightly correlates with neuronal dysfunction and death. Tauopathy is accompanied by increased reactive microglia and astrocytes and increased T cells in the brain, particularly CD8+ cytotoxic T lymphocytes. We previously found that depleting T cells significantly ameliorated tau-mediated neurodegeneration in p.Pro301Ser (P301S) tau transgenic mice expressing human APOE4 (TE4), supporting an active role for T cells in driving tau-mediated neurodegeneration.

Clonally expanded CD8+ T cells constituted a majority of the infiltrating CD3+ T cells (~60-70%) in TE4 brain. Conventional type 1 dendritic cell (cDC1s) are specialized antigen-presenting cells (APCs) that perform antigen cross-presentation, a process that involves presenting exogenously derived antigens on major histocompatibility complex class I (MHC-I) molecules to prime CD8+ T cells. During T cell priming, naive CD8+ T cells receive antigenic, co-stimulatory and cytokine signals from APCs, driving their differentiation into effector cells that subsequently migrate to peripheral tissues to execute their immune functions.

Here, we investigated the role of cDC1s in tau-mediated neurodegeneration by genetically ablating cDC1s or disrupting their antigen cross-presentation capacity in TE4 mice. Both interventions markedly protected against neurodegeneration and selectively reduced CD8+ T cell accumulation in the brain. Importantly, we found that cDC1-dependent antigen cross-presentation of a brain-derived antigen occurs outside central nervous system tissues, highlighting peripheral antigen presentation as a potential therapeutic target for tauopathies, including Alzheimer's disease.