T Cell Exhaustion and the Role of Infections in Alzheimer's Disease

Is Alzheimer's disease the result of persistent infection, or the interaction of several different persistent infections? If a long-term burden of infection is a primary driver of the development of the condition, it would help to explain why lifestyle factors strongly associated with other age-related conditions, such as obesity and lack of exercise, don't correlate anywhere near as well with Alzheimer's incidence. Given the apparent importance of chronic inflammation in Alzheimer's pathology, one might expect it to be more of a lifestyle condition than is in fact the case. But chronic infection has a different, overlapping incidence, and this may better fit the observed pattern of disease.

Researchers here discuss this view of Alzheimer's disease in the context of their analysis of immune cell populations, finding that T cell exhaustion tends to correlate with the severity of Alzheimer's symptoms. T cell exhaustion is a complex, loosely defined, and not fully understood phenomenon in which an increasing number of T cells respond poorly to antigen presentation. They don't react as aggressively as they should, and immune function is compromised as a consequence. This is distinct from T cell senescence, also a feature of aging. Exhaustion is a state that appears to be reversible, given the right changes in regulatory systems.

T cell exhaustion is associated with cognitive status and amyloid accumulation in Alzheimer's disease

In this study we examined immune system alterations early in the progression to Alzheimer's disease (AD). We observed multiple changes across the peripheral innate and adaptive immune systems associated with amyloid and cognitive status within our aging cohort. In the innate immune system, we observed increased plasmacytoid and myeloid dendritic cells in amyloid positive participants, but these changes were particularly pronounced in those with mild cognitive impairment. We also observed a decrease in total natural killer cells with amyloid positivity. When the adaptive immune system was examined, we observed increases in total T cells and B cells in amyloid positive participants.

To further understand alterations in the T cell pool we used flow cytometry to interrogate T cell differentiation and function. We observed an increase in differentiated CD4+ and CD8+ T cell phenotypes in amyloid positive participants with mild cognitive impairment. Surprisingly, we observed an increase in functional CD4+ and CD8+ T cells in amyloid positive cognitively normal participants, while those from amyloid positive mild cognitive impairment subjects had a dramatic increase in exhausted T cells. Importantly when T cell function was compared to cognitive status as determined by mini-mental state examination (MMSE), patients with the lowest score had the highest number of exhausted cells.

Understanding how inflammation and the immune response control the development of AD is critical to develop new treatments. While AD is a disease of the brain, our results demonstrate changes of the immune system in the blood. The increases in both plasmacytoid and myeloid dendritic cells are suggestive of an ongoing response in amyloid positive participants regardless of cognitive status that precedes dementia.

Given the numerous links between infection, inflammation, and AD our results suggest two models where T cells may be the nexus for disease. In the first, amyloid production is a response to simmering infections in periphery and brain with the multiple chronic pathogens all humans carry. Individuals who have strong T cell function control the replication of these pathogens and remain cognitively normal. This would explain why particpants who have the most functional T cells still have the highest MMSE score. But in individuals who lose T cell function, chronic pathogens reactivate, overstimulate innate responses, particularly type I interferon production, potentially leading to cognitive impairment. This is the model we favor and suggests rejuvenation of T cells by immune checkpoint inhibitors and other treatments may be a plausible ex vivo therapy for AD.

An alternative model posits that the cytokine production by the T cells while participants are cognitively normal drives the development of cognitive impairment. Support for this idea is provided by a recent study that used in vitro cultured stem cell derived neurons, astrocytes, and microglia incubated with healthy peripheral blood mononuclear cells (PBMCs) that showed increased microglial activation and inflammation driven by CD8+ T cells mediated by CXCR3 driven infiltration. While these are important and interesting results there are two reasons that a protective rather than pathogenic role for T cells may be warranted. First, from a teleological point of view the increased function may be a form of resilience helping to stave off disease from chronic innate inflammation as we described earlier. The second, is that several studies have observed an increase in IFN╬│ that is associated with slower symptomatic progression in AD. Discerning between these two models will require a longitudinal study to understand the exact temporal relationship between T cell function, exhaustion, and cognitive function.