Da Mesquita S, Herz J, Wall M, Dykstra T, de Lima KA, Norris GT, Dabhi N, Kennedy T, Baker W, Kipnis J. Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology. Sci Adv. 2021 May;7(21) Print 2021 May PubMed.

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  1. The meningeal lymphatic system and its neuro-immune interactions are of great importance. These regulate processes that range from learning and behavior to neuroinflammation and homeostasis. Aging has been shown to affect meningeal lymphatics and the immune system and is the greatest risk factor for the development of dementias, such as Alzheimer’s disease. Despite its importance, the role of aging in meningeal immunity has not been elucidated.

    In this exciting publication, De Mesquita et al. characterized the meningeal immune profile of old mice. Importantly, this allowed them to identify reduced CCR7 expression on T cells. The authors then discovered that the meningeal T cell composition in CCR7-deficient mice mimics that of aged mice. This deficiency also resulted in impaired glymphatic function, poorer cognition, and increased Aβ deposition in a mouse model of Alzheimer’s disease.

    The observed changes are profound and result in altered microglial and blood endothelial cell transcriptomes. This discovery will further allow us to understand the common mechanisms responsible for aging-associated meningeal disfunction and cognitive decline. This discovery has the potential to be the basis for new therapeutics that target CCR7-mediated egress of cells from the brain in neurodegenerative diseases such as Alzheimer’s disease.

    View all comments by Gary Grajales

  2. Within the last few years, the concept of “immune privilege” of the central nervous system has been revisited and modified. Growing evidence has demonstrated complex interactions between the brain and both the innate and adaptive immune systems that have important implications for development, homeostasis, normal aging, and disease. The meningeal lymphatic system is one major compartment enabling such interactions (Salvador et al., 2021). In this important study, Da Mesquita et al. provide further evidence that its perturbation contributes to aging-related decline of neural function in mice.

    They observed that with normal aging, meningeal CD4+ T cells reduce expression of CCR7, a receptor involved in egress and homing of lymphocytes to the CNS-draining, deep cervical lymph nodes. This was accompanied by increased numbers of CD4+ and CD8+ T cells and a higher proportion of CD4+CD25+FoxP3+ Treg cells in the meninges. Similar alterations were identified in adult-bone-marrow chimeras lacking CCR7 in hematopoietic cells, together with a reduced proportion of T-bethigh CD4+ and CD8+ effector T cells and lower IFNγ expression in the meninges.

    Intriguingly, CCR7 deficiency resulted in a decline of spatial memory and glymphatic function. They also detected downregulation of CCR7 in the 5xFAD mouse model of Alzheimer’s-like disease. CCR7 deficiency exacerbated Aβ accumulation and spatial memory defects, and resulted in transcriptional changes in brain endothelial cells and microglia in the AD model, reflecting increased neuroinflammation. Acute treatment of old mice with anti-CD25 antibodies reduced meningeal Treg numbers and improved spatial memory. Together, these findings indicate that decreased expression of CCR7 and increased Treg responses might contribute to aging-associated cognitive impairment. This has important translational implications.

    The work elegantly complements previous studies demonstrating that IFNγ-producing meningeal CD4+ T cells support cognitive function. However, it also raises important questions regarding the putative causes and mechanisms linking the described aging-related alterations. Our recent work has demonstrated that accumulation of cytotoxic CD8+ T cells in white-matter compartments of the normal aging CNS leads to axon degeneration and contributes to decline of non-spatial memory (Groh et al., 2021). Similarly, a detrimental role of CD8+ T cells has been proposed for Alzheimer’s disease based on findings in patients (Gate et al., 2020) and mice (Unger et al., 2020). Using scRNA-Seq, we also found that different subpopulations of CD8+ CNS-associated T cells expressed Ccr7 (mostly in the CSF and meninges) and downregulated Ifnγ expression with aging, in line with the results of Da Mesquita et al. Yet, IFNγ production by CD8+ T cells has been proposed to impair the proliferation of neural stem cells in the aged ependyma (Dulken et al., 2019). Since the present study showed that CCR7 deficiency and impaired meningeal lymphatic function result in cognitive deficits and neurovascular and microglial activation, it would be highly interesting to also study the effects on parenchymal infiltration of T cells and on neurodegenerative alterations. This might emphasize the distinct roles of CD4+ and CD8+ T cells in aging-related decline of brain function, and provide another example for the complexity of neuro-immune interactions.

    References:

    Salvador AF, de Lima KA, Kipnis J. Neuromodulation by the immune system: a focus on cytokines. Nat Rev Immunol. 2021 Mar 1; PubMed.

    Groh J, Knöpper K, Arampatzi P, Yuan X, Lößlein L, Saliba AE, Kastenmüller W, Martini R. Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Nat Aging 1, 2021, pp. 357–367. Nat Aging.

    Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS, Middeldorp J, Chen K, Lehallier B, Channappa D, De Los Santos MB, McBride A, Pluvinage J, Elahi F, Tam GK, Kim Y, Greicius M, Wagner AD, Aigner L, Galasko DR, Davis MM, Wyss-Coray T. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature. 2020 Jan;577(7790):399-404. Epub 2020 Jan 8 PubMed.

    Unger MS, Li E, Scharnagl L, Poupardin R, Altendorfer B, Mrowetz H, Hutter-Paier B, Weiger TM, Heneka MT, Attems J, Aigner L. CD8+ T-cells infiltrate Alzheimer's disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain Behav Immun. 2020 Oct;89:67-86. Epub 2020 May 29 PubMed.

    Dulken BW, Buckley MT, Navarro Negredo P, Saligrama N, Cayrol R, Leeman DS, George BM, Boutet SC, Hebestreit K, Pluvinage JV, Wyss-Coray T, Weissman IL, Vogel H, Davis MM, Brunet A. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature. 2019 Jul 3; PubMed.

    View all comments by Janos Groh

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