Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E, Wang C, Bao X, Finn MB, Hu H, Shchukina I, Kim MW, Yuede CM, Kipnis J, Artyomov MN, Ulrich JD, Holtzman DM. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023 Mar;615(7953):668-677. Epub 2023 Mar 8 PubMed. Correction.

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  1. This paper is of exceptional conceptual interest to the field of neurodegeneration because it unveils an autoimmune aspect to the neurotoxic effects of the tau that accumulates in the brain.

    T-cells, in cross-talk with microglia, promote neurodegeneration, highlighting an interaction between innate and adaptive immunity, well known to occur in the periphery but not within the brain parenchyma.

    The molecular determinants through which microglia may recruit T-cells, the antigens and related presenting cells underlying the adaptive immune response, as well as the relative contribution of microglia and T-cells to tissue damage, remain to be defined and may provide new therapeutic insights.

    The role of ApoE4 in the process also remains to be elucidated. It may rely on the emerging immunoregulatory role of this apolipoprotein, which is a critical risk determinant in neurodegenerative diseases.

    Overall, this is an important contribution that will inspire much new work on the immunopathology of neurodegeneration.

    View all comments by Costantino Iadecola

  2. This exciting work from Xiaoying Chen, David Holtzman, and colleagues highlights the growing body of work supporting T cell involvement in tauopathy and neurodegenerative disease. The authors show a specific enrichment of CD8 T cells in the parenchyma of mice with tau and APOE4 (though they note APOE4 is not necessary for this induction). It will be interesting to see if similar T cell expansions are present in other forms of tauopathy as well.

    The authors highlight that depleting T cells, or targeting T cell immune checkpoints, slows neurodegeneration. Surprisingly, in amyloid models, it has been shown that genetic immunodeficiency reduces pathology and disease progression (Marsh et al., 2016). From a mechanistic standpoint, it would be interesting to see if genetic loss of T cells still ameliorates tau pathology, although the methods used by Chen et al. are more therapeutically relevant.

    My personal interest lies in understanding the relationship between microglia and T cells. The authors provide good evidence that microglia are presenting antigen to T cells, as has been recognized by the Gate lab. I am looking forward to seeing future studies that investigate the specific TCRs that are expanded and uncover which antigens microglia may be presenting in various neurodegenerative diseases.

    It is puzzling that loss of T cells leads to a decrease in MHCII expression on microglia—clearly, the findings in this manuscript support multiple avenues of research, including a close investigation of the relationships between peripheral immune activation and microgliosis. The authors highlight the importance of type II interferons in microglia/T cell cross talk, but there are many other cytokine ligand pairs that likely contribute to aging and disease. These include CXCL12/CXCR4 as discussed by the Wyss-Coray group (Gate et al., 2021) and type I interferons, which I and others are fervently investigating.

    Looking forward, it will be important to take an unbiased approach in our studies of parenchymal immune interactions in tauopathy and to synthesize data from genetic models and pharmaceutical manipulations.

    References:

    Marsh SE, Abud EM, Lakatos A, Karimzadeh A, Yeung ST, Davtyan H, Fote GM, Lau L, Weinger JG, Lane TE, Inlay MA, Poon WW, Blurton-Jones M. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):E1316-25. Epub 2016 Feb 16 PubMed.

    Gate D, Tapp E, Leventhal O, Shahid M, Nonninger TJ, Yang AC, Strempfl K, Unger MS, Fehlmann T, Oh H, Channappa D, Henderson VW, Keller A, Aigner L, Galasko DR, Davis MM, Poston KL, Wyss-Coray T. CD4+ T cells contribute to neurodegeneration in Lewy body dementia. Science. 2021 Nov 12;374(6569):868-874. Epub 2021 Oct 14 PubMed.

    View all comments by Amanda McQuade

  3. This manuscript provides exciting new data to suggest that T-cells may contribute to neurodegeneration in Alzheimer’s disease and frontotemporal dementia. This important insight could potentially lead to a paradigm shift in our understanding of how the immune system contributes to disease progression, and has the potential to lead to a differentiated set of new therapeutic strategies.

    Advances in our understanding of the human genetic contributors to Alzheimer’s disease over the past 15 years have led to an increased focus on the role of the immune system, but this focus has been largely on the role of microglia as the resident immune cells in the brain. It has been less clear whether the peripheral immune system also contributes to disease progression. Significant effort in recent years has focused on how genetic risk factors influence microglial cell state/function, and how these functions may directly contribute to degeneration.

    This new paper reveals that one function of microglia may be to recruit CD8+ killer T-cells into the CNS, which subsequently drive neurodegeneration, particularly in models with tau pathology. As similar increases in T-cells were observed in brains of Alzheimer’s patients, it is possible that CNS infiltration of this cell type contributes to degeneration and functional decline in patients, as well.

    As the mechanisms that underlie T-cell activation and clonal expansion in the periphery have been extensively studied, this finding has the potential to be rapidly translated into targeted therapies aimed at these mechanisms in the CNS.

    Based on these results, therapeutic approaches targeting T cells are likely to capture the interest of many organizations that are working to develop treatments for Alzheimer’s and FTD, though many questions remain to be solved if this approach is to be effectively translated to the clinic. First, broad suppression of T-cell activation is not likely to be well tolerated in elderly individuals with dementia, and strategies should be investigated that are more selective for the T cell population present in the CNS.

    Second, if microglia indeed act as antigen presenting cells to elicit a T cell response, then effective drugs would likely need to readily (and perhaps selectively) access the CNS in order to be effective. Lastly, biomarkers of the T-cell response that can be used for patient selection or target engagement would be required to clinically de-risk this approach prior to conducting large-scale trials. Nonetheless, this study provides an exciting start to what is sure to be an area of active investigation in the years to come.

    View all comments by Joseph Lewcock

  4. This paper emphasizes once again a paradigm that is becoming increasing clear: different forms of dementia, including Alzheimer’s disease, are not diseases of only the brain, but also involve the immune system and the immune-brain axis. The present study further highlights the complexity of this relationship.

    Specifically, the authors nicely showed that disease pathology in a new mouse model that combines tauopathy with human ApoE-4 expression is associated with detrimental microglia and cytotoxic CD8+ cells; depletion of each of these cell populations reduces disease manifestations. These findings, however, cannot be used as arguments that microglia are always and uniformly detrimental, or that T cells are uniformly harmful, and that these effects are at all stages of the disease.

    The authors used anti-PD-1 antibody as a therapeutic approach, and attribute the beneficial effect of this treatment to the recruitment of regulatory T cells (Tregs) to the brain. A similar mechanism was proposed in another model of tauopathy, in which targeting the PD-1/PD-L1 pathway mitigated disease manifestations, at least in part via the recruitment of monocytes and Tregs (Ben-Yehuda et al., 2021). 

    The efficacy of anti-PD-1/PD-L1 immune checkpoint therapy as a treatment for dementia was also shown in models of dementia driven by amyloidosis (Baruch et al., 2016; Rosenzweig et al., 2019; Zou et al., 2021; Xing et al., 2021; Dvir-Szternfeld et al., 2022). In those studies, the effect was attributed to homing of monocyte-derived macrophages that contributed to dampening local brain inflammation. Interestingly, the same treatment was recently shown to be beneficial in mitigating natural aging-related pathology in mice, through the depletion of senescent cells in several organs (Wang et al., 2022). 

    Much additional work is needed to comprehensively understand the brain’s immunological mechanisms. Nevertheless, these and other recent findings demonstrate the role of systemic immune cells in controlling the development and progression of neurodegeneration.

    We are entering a new era in the search for treatments for Alzheimer’s disease and tauopathy, in which the targets are not necessarily the pathological proteins themselves, but the immune system, which can regulate their accumulation in the brain, and the inflammatory damage associated with proteinopathies.

    References:

    Ben-Yehuda H, Arad M, Peralta Ramos JM, Sharon E, Castellani G, Ferrera S, Cahalon L, Colaiuta SP, Salame TM, Schwartz M. Key role of the CCR2-CCL2 axis in disease modification in a mouse model of tauopathy. Mol Neurodegener. 2021 Jun 25;16(1):39. PubMed.

    Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, Kertser A, David E, Amit I, Schwartz M. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.

    Rosenzweig N, Dvir-Szternfeld R, Tsitsou-Kampeli A, Keren-Shaul H, Ben-Yehuda H, Weill-Raynal P, Cahalon L, Kertser A, Baruch K, Amit I, Weiner A, Schwartz M. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

    Zou Y, Gan CL, Xin Z, Zhang HT, Zhang Q, Lee TH, Pan X, Chen Z. Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer's Disease Mouse Models. Front Cell Dev Biol. 2021;9:769229. Epub 2021 Dec 16 PubMed.

    Xing Z, Zuo Z, Hu D, Zheng X, Wang X, Yuan L, Zhou L, Qi F, Yao Z. Influenza vaccine combined with moderate-dose PD1 blockade reduces amyloid-β accumulation and improves cognition in APP/PS1 mice. Brain Behav Immun. 2021 Jan;91:128-141. Epub 2020 Sep 19 PubMed.

    Dvir-Szternfeld R, Castellani G, Arad M, Cahalon L, Phoebeluc Colaiuta S, Keren-Shaul H, Croese T, Burgaletto C, Baruch K, Ulland T, Colonna M, Weiner A, Amit I, Schwartz M. Alzheimer’s disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse model of amyloidosis. . Nature Aging 2: Jan 2022

    Wang TW, Johmura Y, Suzuki N, Omori S, Migita T, Yamaguchi K, Hatakeyama S, Yamazaki S, Shimizu E, Imoto S, Furukawa Y, Yoshimura A, Nakanishi M. Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes. Nature. 2022 Nov;611(7935):358-364. Epub 2022 Nov 2 PubMed.

    View all comments by Michal Schwartz

  5. This interesting paper highlights that adaptive immunity plays a role in neurodegeneration, particularly Alzheimer's disease. It would be worth investigating if are there any TCRs that interact with microglial antigen-presenting cells. Is there any other antigen involved in this interaction, like TREM2? Autoinflammatory side effects are major setbacks as far as current therapies are concerned. It may be possible that removal of these T-cells either by antibody or small molecule may be therapeutic event. It would be worth investigating the interaction of T-cells with microglia in other mouse models, particularly related to Aβ.

    View all comments by Suhail Rasool

  6. Congratulations to Xiaoying and the Holtzman lab for this very thought-provoking paper. Perhaps there could be some ideas around crossing NOD-SCID mice with tauopathy mice? The NOD-SCID mouse model has a much-weakened adaptive immune response (less T and B cells) but still has its innate immune system intact, and is typically used for cancer xenograft models. In my opinion it is a better model than the strongly immunocompromised ones such as Nu/Nu, but this could also be tried.

    I would also be interested to see how tauopathy mouse models respond to biologic TNF alpha inhibitors, such as Enbrel/etanercept (soluble TNF alpha, Pfizer), Remicade/infliximab (Merck), adalimumab (Humira), golimumab (Janssen), and Cimzia/certolizumab (UCB). Some of these target insoluble TNF alpha, which may not reach certain organs and tissues, such as the iris of the eye, as readily. If epidemiological data is available, persons who have been taking these medicines could also be checked for their prevalence of AD and tauopathies.

    View all comments by Phillip Janowicz

  7. This is an exciting paper that suggests that microglia-T cell crosstalk may promote neurodegeneration in AD. Interestingly, this is only observed in the context of tauopathy, but not Aβ deposition.

    Together with previous reports on the dysregulation of T cell responses in AD, these findings suggest that T cell-targeting therapies, alone or in combination with other approaches, may be of use for the treatment of AD. As with any other provocative findings, follow-up questions should be addressed. For example, the authors mention differences in the T cell responses detected in the parenchyma and the meninges. The authors mostly focused on the pathogenic effects of the parenchymal T cell response. However, in future studies it would be useful to interrogate the role of the meningeal response in AD pathology. In addition, a deeper mapping of the specificity of these pathogenic T cells may guide antigen-specific interventions for AD, for example based on tolerogenic nanoparticles as described for multiple sclerosis (Kenison et al., 2020). 

    References:

    Kenison JE, Jhaveri A, Li Z, Khadse N, Tjon E, Tezza S, Nowakowska D, Plasencia A, Stanton VP Jr, Sherr DH, Quintana FJ. Tolerogenic nanoparticles suppress central nervous system inflammation. Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):32017-32028. Epub 2020 Nov 25 PubMed.

    View all comments by Francisco Quintana

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