Age-associated changes in CD4 T-cell functionality have been linked to chronic inflammation and decreased immunity. However, a detailed characterization of CD4 T cell phenotypes that could explain these dysregulated functional properties is lacking. We used single-cell RNA sequencing and multidimensional protein analyses to profile thousands of CD4 T cells obtained from young and old mice. We found that the landscape of CD4 T cell subsets differs markedly between young and old mice, such that three cell subsets—exhausted, cytotoxic, and activated regulatory T cells (aT_regs)—appear rarely in young mice but gradually accumulate with age. Most unexpected were the extreme pro- and anti-inflammatory phenotypes of cytotoxic CD4 T cells and aT_regs, respectively. These findings provide a comprehensive view of the dynamic reorganization of the CD4 T cell milieu with age and illuminate dominant subsets associated with chronic inflammation and immunity decline, suggesting new therapeutic avenues for age-related diseases.

Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7–9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis onPGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell‐derived microglia, advances ofTREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. image Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7–9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell‐derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article.

Vaccination against amyloid β-peptide (Aβ) has been shown to be successful in reducing Aβ burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although Aβ immunization did not show T cell infiltrates in the brain of these mice, an Aβ vaccination trial resulted in meningoencephalitis in 6% of patients with AD. Here, we explore the characteristics and specificity of Aβ-induced, T cell-mediated encephalitis in a mouse model of the disease. We demonstrate that a strong Aβ-specific T cell response is critically dependent on the immunizing T cell epitope and that epitopes differ depending on MHC genetic background. Moreover, we show that a single immunization with the dominant T cell epitope Aβ10–24 induced transient meningoencephalitis only in amyloid precursor protein (APP)-transgenic (Tg) mice expressing limited amounts of IFN-γ under an myelin basic protein (MBP) promoter. Furthermore, immune infiltrates were targeted primarily to sites of Aβ plaques in the brain and were associated with clearance of Aβ. Immune infiltrates were not targeted to the spinal cord, consistent with what was observed in AD patients vaccinated with Aβ. Using primary cultures of microglia, we show that IFN-γ enhanced clearance of Aβ, microglia, and T cell motility, and microglia-T cell immunological synapse formation. Our study demonstrates that limited expression of IFN-γ in the brain, as observed during normal brain aging, is essential to promote T cell-mediated immune infiltrates after Aβ immunization and provides a model to investigate both the beneficial and detrimental effects of Aβ-specific T cells.

Microglia play a key role in innate immunity in Alzheimer disease (AD), but their role as antigen-presenting cells is as yet unclear. Here we found that amyloid β peptide (Aβ)-specific T helper 1 (Aβ-Th1 cells) T cells polarized to secrete interferon-γ and intracerebroventricularly (ICV) injected to the 5XFAD mouse model of AD induced the differentiation of major histocompatibility complex class II (MHCII)+ microglia with distinct morphology and enhanced plaque clearance capacity than MHCII- microglia. Notably, 5XFAD mice lacking MHCII exhibited an enhanced amyloid pathology in the brain along with exacerbated innate inflammation and reduced phagocytic capacity. Using a bone marrow chimera mouse model, we showed that infiltrating macrophages did not differentiate to MHCII+ cells following ICV injection of Aβ-Th1 cells and did not support T cell-mediated amyloid clearance. Overall, we demonstrate that CD4 T cells induce a P2ry12+ MHCII+ subset of microglia, which play a key role in T cell-mediated effector functions that abrogate AD-like pathology.