Brain regulatory T cells

Liston, Adrian; Pasciuto, Emanuela; Fitzgerald, Denise C.; Yshii, Lidia

doi:10.1038/s41577-023-00960-z

Cited by 10 publications

(3 citation statements)

References 104 publications

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“…Consideration of additional biological modalities may also offer a more systematic assessment of rejuvenation or accelerated aging. For example, different types of T cells have been shown to have either beneficial or detrimental effects on the brain 2,75,109,[145][146][147][148][149][150][151][152][153][154][155] , particularly in response to injury or disease 29,156,157 . Disentangling the proximity effect of heterogeneous T cell populations in diverse regions could give a better understanding of neuroimmune interactions during aging.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation

Sun,

Zhou,

Hauptschein

et al. 2024

Preprint

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Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk. Brain aging is complex and accompanied by many cellular changes. However, the influence that aged cells have on neighboring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in aging tissues have not yet been developed. Here, we generate spatiotemporal data at single-cell resolution for the mouse brain across lifespan, and we develop the first machine learning models based on spatial transcriptomics ('spatial aging clocks') to reveal cell proximity effects during brain aging and rejuvenation. We collect a single-cell spatial transcriptomics brain atlas of 4.2 million cells from 20 distinct ages and across two rejuvenating interventions--exercise and partial reprogramming. We identify spatial and cell type-specific transcriptomic fingerprints of aging, rejuvenation, and disease, including for rare cell types. Using spatial aging clocks and deep learning models, we find that T cells, which infiltrate the brain with age, have a striking pro-aging proximity effect on neighboring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating effect on neighboring cells. By developing computational tools to identify mediators of these proximity effects, we find that pro-aging T cells trigger a local inflammatory response likely via interferon-gamma; whereas pro-rejuvenating neural stem cells impact the metabolism of neighboring cells possibly via growth factors (e.g. vascular endothelial growth factor) and extracellular vesicles, and we experimentally validate some of these predictions. These results suggest that rare cells can have a drastic influence on their neighbors and could be targeted to counter tissue aging. We anticipate that these spatial aging clocks will not only allow scalable assessment of the efficacy of interventions for aging and disease but also represent a new tool for studying cell-cell interactions in many spatial contexts.

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Section: Discussionmentioning

confidence: 99%

Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation

Sun,

Zhou,

Hauptschein

et al. 2024

Preprint

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“…In mice, IL-2LD has shown efficacy in the treatment of numerous experimental brain disorders underpinned by neuroinflammation, including in models of multiple sclerosis (MS) (McIntyre et al, 2020), Alzheimer disease (AD) (Alves et al, 2017), ALS (Camu et al, 2020;Nigel Leigh et al, 2023), and brain trauma (Liston et al, 2023). In a murine chronic stress-induced model of depression, IL-2LD corrected the Th17/Treg balance and peripheral tags of low-grade inflammation, and attenuated depression-like behaviours (Liston et al, 2023). These positive effects of boosting Tregs in neuroinflammatory settings could arise from the control of inflammation as well as from an improved tissue regeneration.…”

Section: Introductionmentioning

confidence: 99%

“…These positive effects of boosting Tregs in neuroinflammatory settings could arise from the control of inflammation as well as from an improved tissue regeneration. Indeed, another major role of Tregs is to favour tissue regeneration, as documented in the lung, the muscle and the brain, for example (Mock et al, 2014;Villalta et al, 2014;Becker et al, 2023;Liston et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Leboyer,

Foiselle,

Tchitchek

et al. 2024

Preprint

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Immune abnormalities including an insufficiency of regulatory T cells (Treg) and increased blood-based inflammatory markers have been observed in bipolar disorders (BD), particularly during depression. As Tregs are pivotal to control inflammation, Treg stimulation by low-dose IL-2 (IL-2LD) could have a therapeutic impact on bipolar depression. We performed a randomized, double-blind, placebo-controlled (2 active: 1 placebo) proof-of-concept trial of add-on IL-2LDin patients with bipolar depression. Patients received a placebo or IL-2LD(1MIU) once a day for 5 days, and then once a week for 4 weeks starting on week 2. The primary objective was to demonstrate a biological Treg response to IL-2LDassessed by fold increase in Treg percentage of CD4+ cells from baseline to day 5. Secondary objectives included safety assessment and mood improvement throughout the study period. This trial is registered with ClinicalTrials.gov, numberNCT04133233. Fourteen patients with bipolar depression were included, with 4 receiving placebo and 10 IL-2LD. Baseline clinical and biological characteristics were balanced between groups. The primary evaluation criterion was met, with IL-2LDexpanding 1.17 [95% CI 1.01-1.34] vs 1.01 [95% CI 0.90 - 1.12] (p=0.0421) and activating Tregs. Secondary evaluation criteria were also met with significant improvements of depressive symptoms and global functioning from day-15 onwards in the IL-2LDtreated patients. The treatment was well-tolerated, with no serious adverse events related to treatment. This proof-of-concept trial shows that stimulating Tregs in patients with bipolar depression is safe and associated with clinical improvements. This supports a pathophysiological role of inflammation in BD and warrants pursuing the evaluation of IL-2LDas an adjunct treatment of major mood disorders.

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Interleukin-2 immunotherapy reveals human regulatory T cell subsets with distinct functional and tissue-homing characteristics

Raeber,

Caspar,

Zurbuchen

et al. 2024

Immunity

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Brain regulatory T cells

Cited by 10 publications

References 104 publications

Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation

Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation

Low-dose interleukin-2 in patients with bipolar depression: a phase 2 randomised double-blind placebo-controlled trial

Interleukin-2 immunotherapy reveals human regulatory T cell subsets with distinct functional and tissue-homing characteristics

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