T Cells in the Brain Goad Microglia to Muddle Myelin

The idea that infiltrating T cells contribute to a neurodegenerative environment in aging and in Alzheimer’s disease has gotten another boost. In the June 27 Nature Neuroscience, scientists led by Mikael Simons, Technical University Munich, reported that in mouse models of amyloidosis, CD8+ T cells stir a subset of interferon-γ-responsive microglia, which, in turn, hinder oligodendrocytes, leaving myelin to unfold, split, and degenerate. Knocking down the T cells or the microglia reverses the damage, while leaving amyloid untouched. The work indicates that the adaptive immune system may trigger the degradation of myelin and white matter seen in AD and other neurodegenerative diseases.

  • In AD, CD8+ T cells infiltrate the brain and release interferon-γ.
  • This stirs highly phagocytic microglia that attack myelin.
  • The microglia cripple oligodendrocytes compromising myelin repair.

“This work provides compelling evidence that CD8+ T cells and microglia interactions are pivotal in the myelin pathology observed in Alzheimer’s disease,” wrote Mehdi Jorfi and Rudolph Tanzi of Massachusetts General Hospital in Boston.

Xiaoying Chen and David Holtzman at Washington University in St. Louis praised the study. “These results beautifully highlight the specific importance of microglia-T cell interactions in white-matter damage, an important target for preserving and maintaining normal axonal function and cognition,” they wrote (comments below).

Myelin sheaths that insulate neurons in the white matter degrade as a part of normal aging and, to a greater extent, during neurodegenerative disease. Scientists do not know why this happens, but with age, oligodendrocytes—the cells responsible for maintaining myelin—morph into states associated with myelin damage and disease, including those producing the serine protease inhibitor Serpina3n (Jan 2020 news; Fissolo et al., 2021; Kenigsbuch et al., 2022).

To better understand any role these oligodendrocytes play in myelin degradation during AD, co-first authors Shreeya Kedia of TUM and Hao Ji at Ludwig-Maximilian-University, also in Munich, turned to mouse models of amyloidosis. First, the scientists analyzed brain tissue from 5xFAD and APPNL-G-F mice when their amyloid plaque load had plateaued, at 10 and 12 months old, respectively. They spotted Serpina3n-positive oligodendrocytes and oligodendrocyte precursor cells (OPCs) in the white and gray matter, whereas no, or very few, of these cells showed up in age-matched wild-type mice.

Kedia and colleagues found the Serpina3n oligodendrocytes had swelled with myelin basic protein (MBP), and their processes had fragmented, suggesting they were overwhelmed with myelin. Scanning electron microscopy showed abnormal myelin structures, including outfolds, splits, fragments, and even an excess in places (image below).

Myelin Mayhem. White and gray matter of 10-month-old 5xFAD mice had various kinds of myelin damage and axons swollen with myelin. [Courtesy of Kedia et al., Nature Neuroscience, 2024.]

Simons thinks that OPC proliferation hints at a regenerative response to neuroinflammation that fails because maturing oligodendrocytes malfunction and die. What would cause the inflammation? In the 10-month-old 5xFAD and 12-month-old APPNL-G-F mice, the authors found an infiltration of CD8+ T cells in the white and gray matter. Did these mess with the oligodendrocytes and the myelin? Injecting an anti-CD8 antibody into the abdomens of 6-month-old 5xFAD mice—the age when CD8+ T cells appear in gray matter—led to two-thirds fewer Serpina3n oligodendrocytes in the cortex and one-third fewer myelin abnormalities than in controls six weeks later (image below). The opposite was true in 5xFAD animals injected with anti-PD-1 and anti-CTLA-4 antibodies, which release the brakes on immune checkpoints—these mice cranked out more CD8+ T cells and myelin damage jumped about 50 percent. Likewise, APPNL-G-F mice crossed with Rag1 knockout mice, which can’t make B and T cells, had normal myelin. Taken together, these results suggest that the T cells exacerbate oligodendrocyte failure and myelin abnormalities.

Notably, the amyloid load remained unchanged whether CD8+ T cells were depleted or multiplied, suggesting that myelin and amyloid pathology are independent.

Meddling T Cells. Scanning electron microscopy found abnormal myelin (green, top left) in the brains of 5xFAD mice. Oligodendrocytes expressed Serpina3n (white, middle left). When given an anti-CD8 antibody (right column), myelin returned mostly to normal, and the disease-associated oligodendrocytes diminished. [Courtesy of Kedia et al., Nature Neuroscience, 2024.]

How did the CD8+ T cells damage myelin? The scientists suspected microglia were involved. Single-cell RNA sequencing teased out nine types of microglia in 5xFAD mice, including homeostatic, interferon-responsive, and disease-associated (DAM). A subset of the latter, expressing many MHC-II genes, caught the researchers' attention because these cells are highly active and phagocytic. They believe these are in an advanced stage of activation. APPNL-G-F/Rag1 KO mice, and 5xFAD mice given the anti-CD8 antibody had 70 percent fewer MHC-II-positive DAMs than APPNL-G-F and 5xFAD controls. On the other hand, 5xFAD mice given immune checkpoint blockers had twice as many CD8+ T cells, and twice as many MHC-II-positive DAMs.

In 5xFAD brain slices, these MHC-II-positive DAMs were stuffed with MBP, and, when the cells were added to brain slices from wild-type mice, they attacked and engulfed the protein there. Within 5xFAD brain slices, cells next to CD8+ T cells turned up expression of MHC-II genes. Similarly, in hippocampal tissue from people who had had AD, 45 percent of CD8+ T cells were within 50 microns of MHC-II-positive myeloid cells.

The authors think CD8+ T cells stir microglia via interferon-γ (IFNg) because the leukocytes crank out this cytokine, and it induces MHC-II expression (Bhat et al., 2017; Steimle et al., 1994). Indeed, the MHC-II-positive microglia turned on interferon-responsive genes. In vitro, IFNγ roused wild-type microglia to express MHC-II, while injected into 5xFAD mice, it almost doubled MHC-II-positive microglia.

In contrast, giving 5xFAD mice the IFN pathway blocker baricitinib for 12 weeks halved myelin abnormalities even though CD8+ T cell numbers stayed elevated. The baricitinib-treated animals escaped from a Barnes maze faster than controls, as did mice given the anti-CD8 antibody. The data indicate that these myelin deficits have physiological consequences and align with the idea that myelination supports memory (Feb 2020 news).

On that note, Alma Mohebiany and Renzo Mancuso, VIB-Center for Molecular Neurology, Antwerp, Belgium, were intrigued. “Further studies are needed to determine whether CD8 T cells play a region-specific role in how they promote or prevent pathology,” they wrote. “However, there are still interesting implications for the treatment of AD, in that blocking inflammation-induced microglia activation could slow down of learning or memory deficits through preservation of white matter.” (Comment below.)

“Overall, [these results] suggest that targeting the interactions between CD8+ T cells and microglia, or modulating specific interferon pathways, could open new avenues for delaying or halting the progression of AD,” wrote Jorfi and Tanzi.—Chelsea Weidman Burke

Comments

  1. This work provides compelling evidence that CD8+ T cells and microglia interactions are pivotal in the myelin pathology observed in Alzheimer’s disease (AD). Using the 5xFAD mouse model, the authors demonstrated that CD8+ T cells trigger microglial activation through interferon signaling. The activated microglia, characterized by high MHC-II expression, are responsible for damaging myelin, thereby exacerbating neurodegeneration. These findings align with, and expand upon, previous studies indicating the crucial role of adaptive immune cells, particularly CD8+ T cells, in AD pathology.

    Our recent work also supports the notion that CD8+ T cells exacerbate Alzheimer’s neuropathology. In our three-dimensional human neuroimmune axis model, we observed similar detrimental effects of infiltrating CD8+ T cells and their interactions with microglia in driving AD neuropathogenesis (Jorfi et al., 2023). Both studies underscore the significance of the immune system’s role in neurodegenerative diseases and highlight potential therapeutic targets. Additionally, the findings also resonate with those of Chen et al., which illustrated that microglia-mediated T-cell infiltration drives neurodegeneration in tauopathy (Chen et al., 2023). Further supporting evidence also comes from Kaya et al., who demonstrated that CD8+ T-cell induced interferon-responsive oligodendrocytes and microglia in white matter aging (Kaya et al., 2022). The convergence of these studies suggests a broader mechanism, wherein peripheral adaptive immune cells and brain-resident innate immune cells contribute to various forms of neurodegeneration.

    The therapeutic implications of these findings are substantial. The authors found that depleting CD8+ T cells in the 5xFAD mouse model led to reduced myelin abnormalities and improved cognitive functions. Conversely, administering antibodies to PD-1 or CTLA-4 immune checkpoint inhibitors resulted in an increase in CD8+ T cells and myelin abnormalities in the 5xFAD mouse model. This provides compelling evidence for the role of CD8+ T cells in amplifying myelin pathology. Depletion of CD8+ T cells also reduced MHC-II+ microglial cells in the brains of 5xFAD mice. Using single-cell analysis, the depletion of CD8+ T cells in 5xFAD mice significantly decreased the DAM subpopulation enriched in MHC-II genes. Additionally, the authors found that IFNγ increased MHC-II expression and myelin-damaging activity in microglia. At the same time, treatment with baricitinib, an interferon pathway blocker, reduced these effects, resulting in decreased myelin abnormalities and improved cognitive function in 5xFAD mice.

    Overall, this suggests that targeting the interactions between CD8+ T cells and microglia, or modulating specific interferon pathways, could open new avenues for delaying or halting the progression of AD. The study also revealed that interferon-responsive microglia, influenced by CD8+ T cells, are critical in the progression of myelin damage in AD. Previously, we also showed that infiltrating CD8+ T cells activate interferon-associated pathways in microglia (Jorfi et al., 2023). This adds another layer of complexity to the understanding of microglial roles in neurodegeneration, showing that specific immune pathways can directly impact myelin integrity. Given the complexity of the involvement of neuroimmune interactions in AD, future research should focus on elucidating the detailed underlying mechanisms of these interactions and developing precise interventions.

    References:

    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.

    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.

    Kaya T, Mattugini N, Liu L, Ji H, Cantuti-Castelvetri L, Wu J, Schifferer M, Groh J, Martini R, Besson-Girard S, Kaji S, Liesz A, Gokce O, Simons M. CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging. Nat Neurosci. 2022 Nov;25(11):1446-1457. Epub 2022 Oct 24 PubMed.

    View all comments by Mehdi Jorfi View all comments by Rudy Tanzi

  2. There is strong evidence that both the innate and adaptive immune responses contribute to different aspects of Alzheimer’s disease (AD) development and progression. The role of immune responses and their interaction with myelinating oligodendrocytes remain to be addressed. Targeting inflammation against abnormal myelination could hold significant therapeutic promise for AD. This work, led by the Simons and Gokce groups, reported: 1. abnormal myelin ultrastructure in the presence of amyloid; 2. CD8+ T cells play a role in amplifying oligodendrocyte and myelin damage; 3. CD8+ T cells induce myelin pathology by microglial activation; 4. depletion of T cells or microglia, and blocking interferon or JAK signaling, protects against myelin pathology.

    We and other groups showed that the removal and modulation of T cells, or T cell-mediated microglia function, rescued many aspects of neurodegeneration, particularly related to tau. However, the role of T cells in white-matter injury related to AD has ever been addressed. In regard to the current work, while replication in other mouse models and human samples at different Braak stages needs to be explored, finding modulated innate/adaptive immune interactions in amyloid-related white-matter injury in AD indicates that targeted immunotherapy would provide novel strategies for this important aspect of AD neuropathology.

    The team previously identified white-matter-associated microglia (WAMs). WAMs are Trem2-dependent like disease-associated microglia (DAMs) but have ApoE-independent activation during aging. The function of ApoE in microglia in aging and in white-matter injury in AD is an interesting open question for the future. Accordingly, monitoring microglial state transitions and developing specific compounds targeting microglial-mediated neuroimmune response pathways might serve as ways to stage AD and halt its progression.

    Overall, these, and other recent findings, demonstrate the role of immune cells in controlling the development and progression of neurodegeneration. These results beautifully highlight the specific importance of microglia-T cell interactions in white-matter damage, an important target for preserving and maintaining normal axonal function and cognition.

    View all comments by Xiaoying Chen View all comments by David Holtzman

  3. The study from Kedia et al. examines the role of brain-infiltrating CD8+ T cells in promoting white-matter damage. Using two models of Alzheimer’s disease (5XFAD and AppNL-G-F), removing CD8+ T cells reduced myelin abnormalities, and had positive effects on learning and behavior. In the reverse experiment, blocking immune checkpoint inhibitors led to exacerbated myelin damage and anxiety behavior. The authors further showed in the 5xFAD mice that CD8+ T cells induce highly activated microglia, characterized by strong upregulation of MHC-II markers. MHC-II microglia are in proximity to infiltrating CD8+ T cells both in the 5xFAD and human brain. Pharmacological inhibition of the IFN-response pathway in 5xFAD mice reduced myelin damage and improved learning deficits, associated with a decrease in the numbers of IFN-responding microglia.

    This paper suggests that brain-infiltrating CD8+ T cells in AD can abnormally activate microglia, pushing them into a myelin-damaging state. Evidently, further studies are needed to determine whether CD8+ T cells play a region-specific role in how they promote or prevent pathology in AD and whether similar mechanisms indeed are present in humans. However, there are still interesting implications for the treatment of AD, in that blocking inflammation-induced microglia activation could slow down of learning or memory deficits through preservation of white matter. 

    The role of CD8+ T cells in AD has garnered much interest over the last several years. Previous studies have shown conflicting roles of CD8+T cells, due to the models used (Su et al., 2023; Chen et al., 2023). In contrast to this study, for instance, the lack of CD8+ T cells in 5xFAD mice crossed to Tcr⍺-/- mice, led to an increase in amyloid plaque load and increased pathology (Su et al., 2023). However, these mice do not have normal T cell populations from birth, whereas specific antibody-mediated CD8+ T cell depletion as used by Kedia et al. is relatively short-term and specific. It would be interesting to see whether, with CD8 T cells out of the picture, other immune cells, such as regulatory CD4+ T cells, dominate the responses in the 5xFAD brains and contribute to the amelioration.

    References:

    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.

    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.

    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.

    Su W, Saravia J, Risch I, Rankin S, Guy C, Chapman NM, Shi H, Sun Y, Kc A, Li W, Huang H, Lim SA, Hu H, Wang Y, Liu D, Jiao Y, Chen PC, Soliman H, Yan KK, Zhang J, Vogel P, Liu X, Serrano GE, Beach TG, Yu J, Peng J, Chi H. CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology. Nat Immunol. 2023 Oct;24(10):1735-1747. Epub 2023 Sep 7 PubMed.

    View all comments by Alma Mohebiany View all comments by Renzo Mancuso
    • User Profile Image David Gate
      Feinberg School of Medicine, Northwestern University
    • Posted:

    This is yet another impressive study on the impact of brain-penetrant T cells on white matter. As a follow-up to their noteworthy 2022 publication, in which they demonstrated that T cells accumulate in white matter with aging (Kaya et al., 2022), the Simons group and their collaborators report that cerebral amyloidosis promotes CD8+ T cell infiltration in mice. These T cells engage microglia, which become inflamed and damage white matter. This mechanism is harmonious, given that Alzheimer's disease patients incur white-matter damage and accumulate CD8+ T cells in their brains (Gate et al., 2020; Chen et al., 2023). Overall, I find the study of very high quality. The publication would benefit from some human evidence to assuage the concern that the results may be specific to mouse models of cerebral amyloidosis.

    References:

    Kaya T, Mattugini N, Liu L, Ji H, Cantuti-Castelvetri L, Wu J, Schifferer M, Groh J, Martini R, Besson-Girard S, Kaji S, Liesz A, Gokce O, Simons M. CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging. Nat Neurosci. 2022 Nov;25(11):1446-1457. Epub 2022 Oct 24 PubMed.

    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.

    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.

    View all comments by David Gate

  5. This study by Kedia et al. adds to the growing evidence that the CD8+ T cell compartment is associated with, and possibly even actively involved in, AD pathology. The phenomenon of elevated numbers of CD8+ T cells in postmortem AD brain tissue has been known for a long time (Itagaki et al. 1988; Togo et al., 2002). Additionally, more recent studies observed an increased abundance of CD8 T cells, specifically of the TEMRA/effector subtype, in peripheral blood and CSF of individuals with AD pathology (Gate et al., 2020; Gericke et al., 2023). However, the antigen target and function of these AD-associated CD8+ T cells are not yet fully understood. This study provides a possible mechanism of how these cells might contribute to neuronal damage in AD.

    While the data nicely show how CD8+ T cells might trigger myelin damage via microglial activation in amyloidosis mouse models, they are not proof that amyloidosis itself triggers oligodendrocyte and myelin damage, as stated in the abstract. Another recent study by Chen et al. from 2023 states that CD8 T cells are associated with tauopathy and neuronal loss, highlighting the fact that the antigen target that triggers the recruitment of these CD8 T cells to the brain is still elusive. It will be interesting to see if Kedia et al. will investigate myelin damage in the context of tau pathology, which they did not address here.

    A small, but particularly important detail of this study is the replication of some of the results in a different amyloidosis mouse model. Here, the authors chose APPNL-G-F mice, a knock-in model that retains the effects of elevated Aβ without APP overexpression. This choice helps mitigate some concerns about the non-physiological effects of APP overexpression.

    In conclusion, the authors suggest targeting inflammation in general as therapeutic, but their data actually suggests that a more targeted approach against the specific mode of action of the observed CD8 T cells might be more effective. Furthermore, it would be nice to know which subtype of CD8 T cells is responsible for the observed microglial activation and myelin damage, a question future studies will likely address.

    References:

    Itagaki S, McGeer PL, Akiyama H. Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer's disease brain tissue. Neurosci Lett. 1988 Sep 12;91(3):259-64. PubMed.

    Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, Oda T, Tsuchiya K, Kosaka K. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. J Neuroimmunol. 2002 Mar;124(1-2):83-92. PubMed.

    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.

    Gericke C, Kirabali T, Flury R, Mallone A, Rickenbach C, Kulic L, Tosevski V, Hock C, Nitsch RM, Treyer V, Ferretti MT, Gietl A. Early β-amyloid accumulation in the brain is associated with peripheral T cell alterations. Alzheimers Dement. 2023 Jun 14; PubMed.

    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.

    View all comments by Christoph Gericke

  6. This elegant paper from Mikael Simons’ lab focuses on a less-studied pathological feature in Alzheimer’s disease (AD)—myelin damage—and it provides mechanistic insights into the interplay between the innate and adaptive immune systems that mediate this process. White-matter lesions have been demonstrated in AD cases by neuroimaging studies (Nasrabady et al., 2018), and recent single-cell profiling data also point to drastic gene expression changes in oligodendrocyte lineage cells (Mathys et al., 2019), raising questions about the underlying cellular and molecular mechanisms driving myelin abnormalities.

    This study builds on recent seminal work from the Simons lab, which showed that CD8+ T cells trigger interferon-responsive oligodendrocytes and microglia, causing white matter deficits in the aging brain (Kaya et al., 2022). Meanwhile, it has been established that both innate and adaptive immune cells, such as microglia and T cells, are involved in AD pathogenesis (Chen et al., 2023; Gate et al., 2020; Leng and Edison, 2021). It is logical to ask whether similar components are in play to induce myelin damage in AD, and if so, through what mechanisms.

    Indeed, using a mouse model of amyloidosis (5xFAD), Kedia et al. first confirm the existence of myelin abnormalities, which worsen over time, in animals as young as 4 months old. Interestingly, ablation of either CD8+ T cells or microglia alleviates the myelin deficit and improves behavioral outcomes, suggesting that both cell types are implicated in the white matter pathology.

    It is known that CD8+ T cells and microglia interact with each other in the context of AD (Chen et al., 2023). However, the key question is which comes first. Several lines of evidence support that CD8+ T cells trigger microglial activation: (1) In CD8+ T cell depletion, MHC-II+ IFN+ microglia are diminished, whereas in microglia depletion, CD8+ T cells remain unchanged; (2) CD8+ T cells produce interferon-γ, and the relevant microglia population expresses interferon-responsive genes; (3) CD8+ T cells and MHC-II+ IFN+ microglia are in close proximity; (4) manipulation of IFN-γ alters microglial function and myelin pathology.  This last point also explains how microglial activation may cause myelin damage through phagocytosis. Therefore, this paper delineates a series of critical events that have attracted intense research interest in recent years and provides a satisfying answer to a long-standing question in the field regarding white-matter lesions observed in AD.

    This work has important implications and raises many new questions. For example, since it has been shown that myelin dysfunction drives Aβ deposition (Depp et al., 2023), this paper revealing that amyloidosis leads to myelin damage points to a possible loop perpetuating AD pathology. In addition, interferon-γ signaling has been shown to be neuroprotective in AD via other mechanisms (He et al., 2020; Yin et al., 2023). How are these diverse functions implicated in the broader context of potential treatments? Lastly, CD8+ T cells have been shown to drive neurodegeneration in tauopathy, and their infiltration seems to be mediated by microglia (Chen et al., 2023). Are the interactions between microglia and T cells manifested differently depending on AD pathologies, different microglial populations, disease stages, or something else?

    References:

    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.

    Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Nazarenko T, Overhoff K, Steixner-Kumar AA, Subramanian S, Arinrad S, Ruhwedel T, Möbius W, Göbbels S, Saher G, Werner HB, Damkou A, Zampar S, Wirths O, Thalmann M, Simons M, Saito T, Saido T, Krueger-Burg D, Kawaguchi R, Willem M, Haass C, Geschwind D, Ehrenreich H, Stassart R, Nave KA. Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease. Nature. 2023 Jun;618(7964):349-357. Epub 2023 May 31 PubMed.

    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.

    He Z, Yang Y, Xing Z, Zuo Z, Wang R, Gu H, Qi F, Yao Z. Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice. Cell Death Dis. 2020 Jun 8;11(6):440. PubMed.

    Kaya T, Mattugini N, Liu L, Ji H, Cantuti-Castelvetri L, Wu J, Schifferer M, Groh J, Martini R, Besson-Girard S, Kaji S, Liesz A, Gokce O, Simons M. CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging. Nat Neurosci. 2022 Nov;25(11):1446-1457. Epub 2022 Oct 24 PubMed.

    Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?. Nat Rev Neurol. 2021 Mar;17(3):157-172. Epub 2020 Dec 14 PubMed.

    Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, Menon M, He L, Abdurrob F, Jiang X, Martorell AJ, Ransohoff RM, Hafler BP, Bennett DA, Kellis M, Tsai LH. Single-cell transcriptomic analysis of Alzheimer's disease. Nature. 2019 Jun;570(7761):332-337. Epub 2019 May 1 PubMed.

    Nasrabady SE, Rizvi B, Goldman JE, Brickman AM. White matter changes in Alzheimer's disease: a focus on myelin and oligodendrocytes. Acta Neuropathol Commun. 2018 Mar 2;6(1):22. PubMed.

    Yin Z, Herron S, Silveira S, Kleemann K, Gauthier C, Mallah D, Cheng Y, Margeta MA, Pitts KM, Barry JL, Subramanian A, Shorey H, Brandao W, Durao A, Delpech JC, Madore C, Jedrychowski M, Ajay AK, Murugaiyan G, Hersh SW, Ikezu S, Ikezu T, Butovsky O. Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease. Nat Neurosci. 2023 Jul;26(7):1196-1207. Epub 2023 Jun 8 PubMed.

    View all comments by Qingyun (Tristan) Li

  7. There is no question that CD8+ T cells play a significant role in mouse models of AD pathology. Given the comprehensive presentation of the major findings and conclusions by the colleagues above, we will proceed directly to our comments. 

    In our previous work (Yin et al., 2023), we identified a critical role of IFN-γ in microglia polarization to the pre-MGnD (also known as DAM) phenotype. This polarization is beneficial in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model. Importantly, the genetic deletion of IFN-γ signaling in microglia impaired MGnD induction. Simons' group has effectively demonstrated the critical role of IFN-γ in the induction of DAM. However, this study does not directly support the conclusion that CD8+ T cells promote abnormally interferon-activated microglia.

    The authors reported detecting STAT1+ cells at 4 months of age in 5xFAD mice, yet CD8+ T cells were only observed at 6 months of age, at which point anti-CD8 treatment was initiated. Thus, the source of IFN-γ was not addressed in this context. Furthermore, the authors did not provide direct evidence that IFN-γ, whether in general or specifically derived from CD8+ T cells, is responsible for cognitive decline.

    Previous reports have highlighted the therapeutic potential of IFN-γ in AD models through its effects on microglial activity. In 5xFAD mice, Th1 cells polarized to secrete IFN-γ were shown to limit AD pathology by inducing MHCII+ microglia, which are crucial for modulating the brain's immune response (Mittal et al., 2019). Additionally, intraperitoneal injections of IFN-γ in APP/PS1 mice restored microglial autophagy, leading to reduced pathology and improved cognitive function (He et al., 2020). These findings suggest that IFN-γ can reprogram microglia to adopt a neuroprotective phenotype in AD mice.

    We suggest that future studies focus on the IFN-γ cellular source, dose-response (Butovsky et al., 2006), and timing. Additionally, exploring a different combination of cytokines interacting with IFN-γ produced by differnt immune cells, i.e. CD8 vs Th1 cells, may reveal different or even opposite effects on microglia regulation.

    References:

    Yin Z, Herron S, Silveira S, Kleemann K, Gauthier C, Mallah D, Cheng Y, Margeta MA, Pitts KM, Barry JL, Subramanian A, Shorey H, Brandao W, Durao A, Delpech JC, Madore C, Jedrychowski M, Ajay AK, Murugaiyan G, Hersh SW, Ikezu S, Ikezu T, Butovsky O. Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease. Nat Neurosci. 2023 Jul;26(7):1196-1207. Epub 2023 Jun 8 PubMed.

    Mittal K, Eremenko E, Berner O, Elyahu Y, Strominger I, Apelblat D, Nemirovsky A, Spiegel I, Monsonego A. CD4 T Cells Induce A Subset of MHCII-Expressing Microglia that Attenuates Alzheimer Pathology. iScience. 2019 Jun 28;16:298-311. Epub 2019 May 30 PubMed.

    He Z, Yang Y, Xing Z, Zuo Z, Wang R, Gu H, Qi F, Yao Z. Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice. Cell Death Dis. 2020 Jun 8;11(6):440. PubMed.

    Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006 Jan;31(1):149-60. Epub 2005 Nov 16 PubMed.

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References

News Citations

  1. Human and Mouse Microglia React Differently to Amyloid
  2. New Myelin Makes Memories, but Supply Wanes with Age

Research Models Citations

  1. 5xFAD (B6SJL)
  2. APP NL-G-F Knock-in

Paper Citations

  1. Fissolo N, Matute-Blanch C, Osman M, Costa C, Pinteac R, Miró B, Sanchez A, Brito V, Dujmovic I, Voortman M, Khalil M, Borràs E, Sabidó E, Issazadeh-Navikas S, Montalban X, Comabella Lopez M. CSF SERPINA3 Levels Are Elevated in Patients With Progressive MS. Neurol Neuroimmunol Neuroinflamm. 2021 Mar;8(2) Print 2021 Mar PubMed.
  2. Kenigsbuch M, Bost P, Halevi S, Chang Y, Chen S, Ma Q, Hajbi R, Schwikowski B, Bodenmiller B, Fu H, Schwartz M, Amit I. A shared disease-associated oligodendrocyte signature among multiple CNS pathologies. Nat Neurosci. 2022 Jul;25(7):876-886. Epub 2022 Jun 27 PubMed.
  3. Bhat P, Leggatt G, Waterhouse N, Frazer IH. Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis. 2017 Jun 1;8(6):e2836. PubMed.
  4. Steimle V, Siegrist CA, Mottet A, Lisowska-Grospierre B, Mach B. Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science. 1994 Jul 1;265(5168):106-9. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. Kedia S, Ji H, Feng R, Androvic P, Spieth L, Liu L, Franz J, Zdiarstek H, Anderson KP, Kaboglu C, Liu Q, Mattugini N, Cherif F, Prtvar D, Cantuti-Castelvetri L, Liesz A, Schifferer M, Stadelmann C, Tahirovic S, Gokce O, Simons M. T cell-mediated microglial activation triggers myelin pathology in a mouse model of amyloidosis. Nat Neurosci. 2024 Aug;27(8):1468-1474. Epub 2024 Jun 27 PubMed.

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