Breaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder in which chronic neuroinflammation contributes to disease escalation. Nevertheless, while immunosuppressive drugs have repeatedly failed in treating this disease, recruitment of myeloid cells to the CNS was shown to play a reparative role in animal models. Here we show, using the 5XFAD AD mouse model, that transient depletion of Foxp3+ regulatory T cells (Tregs), or pharmacological inhibition of their activity, is followed by amyloid-β plaque clearance, mitigation of the neuroinflammatory response and reversal of cognitive decline. We further show that transient Treg depletion affects the brain's choroid plexus, a selective gateway for immune cell trafficking to the CNS, and is associated with subsequent recruitment of immunoregulatory cells, including monocyte-derived macrophages and Tregs, to cerebral sites of plaque pathology. Our findings suggest targeting Treg-mediated systemic immunosuppression for treating AD.

The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

“…An important question is how the current data fit with a recent study examining the effects of Tregs on AD pathogenesis (17). Tregs normally serve to suppress the systemic immune system and protect against autoimmune disease (50).…”

“…However, in AD mouse models, it appears that this immunosuppressive activity may be detrimental, impairing the ability of the adaptive immune system to respond to and restrain Aβ pathology. When Tregs are depleted for example, Aβ pathology decreased dramatically, whereas compounds that promote Treg differentiation and function exacerbate pathology (17). In comparison, Rag-5xfAD mice lack not only Tregs but also many other components of the adaptive immune system including CD4 and CD8 T cells, B cells, and plasma cells.…”

“…Our data confirm that IgG alone is sufficient to increase phagocytosis in vitro and that delivery of IgG directly to the brains of Rag-5xfAD mice or into circulation via adoptive transfer can induce plaque clearance. Our study therefore adds to a growing area of research that highlights the importance of the peripheral immune system in CNS function and AD (17,18), and demonstrates the need to better understand how these peripheral cell populations act in concert with microglia to influence the CNS in both normal and diseased conditions.…”

“…However, the adaptive and innate immune systems rarely function independently of each other, and thus cross talk between peripheral and central immunity such as cytokine and chemokine signaling likely plays an important albeit understudied role in AD. In support of this notion, two recent studies demonstrated profound effects of peripherally derived neutrophils and T-regulatory cells (Tregs) on AD pathogenesis (17,18). Despite this exciting recent progress, many of the mechanisms and actions of other peripheral immune cell populations in AD remain unknown, and thus a great a deal of additional study is needed.…”

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…Aducanumab, derived from a naturally occurring human autoantibody against Cu 2+ -modified Aβ aggregates (which are the most neuro toxic Aβ species in the AD brain), showed promise in clearing brain Aβ deposits and improving cognition in a 2016 phase Ib trial 57 . Lymphocytes (including B cells, T cells and natural killer cells) also participate in Aβ clearance via immunoglobulin-mediated adaptive phagocytosis 58,59 . Future studies will help to elucidate the crosstalk between innate immunity and adaptive 169,170 .…”