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Jorfi M, Park J, Hall CK, Lin CJ, Chen M, von Maydell D, Kruskop JM, Kang B, Choi Y, Prokopenko D, Irimia D, Kim DY, Tanzi RE. Infiltrating CD8+ T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model. Nat Neurosci. 2023 Sep;26(9):1489-1504. Epub 2023 Aug 24 PubMed.
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Washington University School of Medicine
Washington University
In this study, the authors developed a three-dimensional human neuroimmune axis model, which includes human stem-cell-derived neurons, astrocytes, and microglia, together with human peripheral immune cells, to model AD pathology and progression. They found that 1) the co-existence of CD8+ T cells and microglia resulted in a synergism that exacerbated neuronal and glial damage; 2) in the presence of infiltrating T cells, microglia were significantly activated in IFN-associated pathways and antigen presentation; 3) CXCL10 and its T cell receptor, CXCR3, played key roles in mediating selective T cell infiltration into the three-dimensional model, and treatment with MAB160, an anti-CXCR3-neutralizing antibody, significantly prevented cellular damage. This comprehensive study illustrates that T cells, and their interactions with glia, significantly contribute to AD-related neurodegeneration.
It is now well recognized that both innate and adaptive immune repones are present in neurodegenerative diseases. In AD, adaptive immunity is an important component in both Aβ and tau pathogenesis (Chen and Holtzman, 2022). Several studies have found an increase of T cells in the CSF, leptomeninges, and hippocampus in AD patient postmortem tissue and in both Aβ and tau mouse models (Gate et al. 2020; Laurent et al., 2017; Merlini et al., 2018). Our study found T cells are markedly increased in the brain of a mouse model of tauopathy as well as in the human AD brain in regions with tauopathy. Immune depletion of T cells significantly ameliorates brain atrophy, neuronal loss, and behavioral impairment (Chen et al., 2023).
Mouse models and human samples pose limitations for monitoring the interaction between peripheral immune cells and brain-resident cells in a high-throughput way. This work provides a useful tool to capture brain-immune interactions in vitro and pave the way for mechanistic studies and drug screening for therapeutics development. For example, it will be extremely interesting to study which specific T cell subpopulations, including but not limited to, effector CD4+ T cells, Treg, cytotoxic CD8+ T cells, exhausted CD8+ T cells, and which immune modulator or checkpoint blockade molecules are essential in AD progression.
This work, together with previously published research in the AD field, raises intriguing questions. Would blocking interactions between microglia and T cells serve as a therapeutic target for preventing neurodegeneration in AD? IFNγ receptors were known to be expressed in both neurons and microglia in the brain (Filiano et al., 2016). We found that in the brains of P301S; APOE4 mice, IFNγ transcripts were enriched in T cells, especially CD8+ T cells. Inhibition of IFNγ significantly ameliorated brain atrophy (Chen et al., 2023). It is interesting to investigate if blocking IFNγ receptors in specific cells, including microglia, would modulate neuroinflammation or would ameliorate neurodegeneration in the setting of amyloid or tau pathology.
This research provides insightful context for immunotherapy and highlights new therapeutic strategies for AD. The authors found key roles of CXCL10 and its receptor CXCR3 in regulating T cell infiltration and neuronal damage. We have found the removal and modulation of T cells rescued tau-linked brain atrophy, highlighting an important role of T cells in neurodegeneration. Several reports also indicate that PDCD1 immune checkpoint blockade decreases cognitive impairment in mouse AD models (Baruch et al., 2016; Kumagai et al. 2020). Future studies could extend immunotherapies for AD by targeting immune signaling, even with engineered immune cells.
References:
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Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, Gadani SP, Turner SD, Weng Z, Peerzade SN, Chen H, Lee KS, Scott MM, Beenhakker MP, Litvak V, Kipnis J. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature. 2016 Jul 21;535(7612):425-9. Epub 2016 Jul 13 PubMed.
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Kumagai S, Togashi Y, Kamada T, Sugiyama E, Nishinakamura H, Takeuchi Y, Vitaly K, Itahashi K, Maeda Y, Matsui S, Shibahara T, Yamashita Y, Irie T, Tsuge A, Fukuoka S, Kawazoe A, Udagawa H, Kirita K, Aokage K, Ishii G, Kuwata T, Nakama K, Kawazu M, Ueno T, Yamazaki N, Goto K, Tsuboi M, Mano H, Doi T, Shitara K, Nishikawa H. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol. 2020 Nov;21(11):1346-1358. Epub 2020 Aug 31 PubMed.
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