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FOXP3-expressing regulatory T cells (T

Background: Alzheimer’s Disease is a neurodegenerative disease with a neuroinflammatory component. Due to the multifunctional capacity of regulatory T cells to prevent and reverse inflammation, regulatory T cells have been proposed as a potential therapeutic in Alzheimer’s Disease, either as a direct cell therapy or through the use of IL2 as a biologic to expand the endogenous population. Methods: Here we characterize the longitudinal immunological changes occurring in T cells in the AppNL-G-F mouse model of Alzheimer’s disease. Results: Age-dependent immunological changes, in both the brain and periphery, occurred in parallel in both AppNL-G-F mice and control AppNL mice. As the endogenous IL2 axis was disturbed with age, we sought to determine the effect of IL2 supplementation on disease progression. Using a genetic model of IL2 provision in the periphery or in the brain, we found that expanding regulatory T cells in either location was unable to alter the progression of key pathological events or behavioral changes. Conclusions: These results suggest that either the AppNL-G-F mouse model does not recapitulate key regulatory T cell-dependent process of Alzheimer’s disease, or that regulatory T cell therapy is not a promising candidate for APP-mutation-driven Alzheimer’s disease.

BackgroundAlzheimer’s Disease is a neurodegenerative disease with a neuroinflammatory component. Due to the multifunctional capacity of regulatory T cells to prevent and reverse inflammation, regulatory T cells have been proposed as a potential therapeutic in Alzheimer’s Disease, either as a direct cell therapy or through the use of IL2 as a biologic to expand the endogenous population.MethodsHere we characterize the longitudinal immunological changes occurring in T cells in the AppNL-G-F mouse model of Alzheimer’s disease.ResultsAge-dependent immunological changes, in both the brain and periphery, occurred in parallel in both AppNL-G-F mice and control AppNL mice. As the endogenous IL2 axis was disturbed with age, we sought to determine the effect of IL2 supplementation on disease progression. Using a genetic model of IL2 provision in the periphery or in the brain, we found that expanding regulatory T cells in either location was unable to alter the progression of key pathological events or behavioral changes.ConclusionThese results suggest that either the AppNL-G-F mouse model does not recapitulate key regulatory T cell-dependent process of Alzheimer’s disease, or that regulatory T cell therapy is not a promising candidate for APP-mutation-driven Alzheimer’s disease.

Cognitive decline is a common pathological outcome during aging, with an ill-defined cellular or molecular basis. Among the cellular changes observed with age are alterations to neuronal plasticity, changes in the glial compartment and the decline of the neurogenic niche. In the recent years, the concept of inflammaging, defined as a low-grade inflammation increasing with age, has emerged as a nexus for age-related diseases. This increase of basal inflammation is also observed in the central nervous system. While not classically considered a neurological cell type, infiltrating T cells increase in the brain with age, and may be responsible for amplification of inflammatory cascades and disruptions to the neurogenic niche. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2-mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here we test a brain-specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments, and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the age-induced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy ageing.

Regulatory T cells (Tregs) control inflammation and maintain immune homeostasis. The well-characterised circulatory population of CD4+Foxp3+ Tregs is effective at preventing autoimmunity and constraining the immune response, through direct and indirect restraint of conventional T cell activation. Recent advances in Treg cell biology have identified tissue-resident Tregs, with tissue-specific functions that contribute to the maintenance of tissue homeostasis and repair. A population of brain-resident Tregs, characterised as CD69+, has recently been identified in the healthy brain of mice and humans, with rapid population expansion observed under a number of neuroinflammatory conditions. During neuroinflammation, brain-resident Tregs have been proposed to control astrogliosis through the production of amphiregulin, polarize microglia into neuroprotective states, and restrain inflammatory responses by releasing IL-10. While protective effects for Tregs have been demonstrated in a number of neuroinflammatory pathologies, a clear demarcation between the role of circulatory and brain-resident Tregs has been difficult to achieve. Here we review the state-of-the-art for brain-resident Treg population, and describe their potential utilization as a therapeutic target across different neuroinflammatory conditions. ispartof: IMMUNOLOGY LETTERS vol:248 pages:26-30 ispartof: location:Netherlands status: published

To improve the anti-tumor efficacy of immune checkpoint inhibitors, numerous combination therapies are under clinical evaluation, including with IL-12 gene therapy. The current study evaluated the simultaneous delivery of the cytokine and checkpoint-inhibiting antibodies by intratumoral DNA electroporation in mice. In the MC38 tumor model, combined administration of plasmids encoding IL-12 and an anti-PD-1 antibody induced significant anti-tumor responses, yet similar to the monotherapies. When treatment was expanded with a DNA-based anti-CTLA-4 antibody, this triple combination significantly delayed tumor growth compared to IL-12 alone and the combination of anti-PD-1 and anti-CTLA-4 antibodies. Despite low drug plasma concentrations, the triple combination enabled significant abscopal effects in contralateral tumors, which was not the case for the other treatments. The DNA-based immunotherapies increased T cell infiltration in electroporated tumors, especially of CD8

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT. ispartof: CELL vol:182 issue:3 pages:625-+ ispartof: location:United States status: published

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities., Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

Central nervous system (CNS) inflammation occurs in a large number of neurological diseases. The type and magnitude of CNS inflammation, as well as the T-cell contribution, vary depending on the disease. Different animal models of neurological diseases have shown that T cells play an important role in CNS inflammation. Furthermore, recent studies of human neurological disorders have indicated a significant role for T cells in disease pathology. Nevertheless, how individual T-cell subsets affect neuronal survival, damage and/or loss remains largely unclear. In this review we discuss the processes by which T cells mediate either beneficial or deleterious effects within the CNS, with emphasis on the direct interaction between T cells and neurons, as occurs in multiple sclerosis, paraneoplastic cerebellar degeneration, and viral encephalitis. The therapeutic approaches targeting T cells and their mediators as treatment for neurological diseases are also described here.