Intruder Alert: Inflammatory T Cells Lurk Near Lewy Bodies, Neurons

Evidence indicates T cells invade the brains of people who have a Lewy body dementia, but scientists do not know how they get in, or what they do there. In the October 14 Science, scientists led by Tony Wyss-Coray, Stanford University, Palo Alto, California, reported that these cells glom onto synuclein aggregates and lurk near dopaminergic neurons that had been flooded with interleukin 17A. T cells excreted IL-17A when exposed to α-synuclein peptides in vitro, suggesting they are the source of this inflammatory cytokine. As for why these T cells sneak into the brain, it appears they may be lured by the chemokine CXCL12, which is elevated in the cerebrospinal fluid of people with LBD. This is the first time researchers have identified possibly reactive T cells adjacent to synuclein aggregates in LBD brains.

  • In LBDs, CD4+ T cells near dopaminergic neurons express IL-17A.
  • The CXCL12 chemokine attracts T cells to the brain.
  • People with higher levels of CXCL12 in the CSF had more axon damage.

Michal Schwartz, Weizmann Institute of Science, Rehovot, Israel, called the work comprehensive and elegant. “I am pleased that we are entering into a new era of appreciation for brain-immune system interactions,” she told Alzforum. Patrik Brundin, Van Andel Institute, Michigan, agreed. He noted that immune system responses, which were traditionally seen as responding to neurodegeneration, are now thought of as a potential driver of synucleinopathies (full comment below).

T cells had already been spotted in brain tissue taken postmortem from people who had had dementia with Lewy bodies (DLB) or Parkinson’s disease (Amin et al., 2020; Galiano-Landeira et al., 2020). T cells that recognize α-synuclein have also been isolated from the blood of people with PD, but researchers have been unable to confirm T cells interact with α-synuclein in the brain—until now (Jun 2017 news; Lindestam Arlehamn et al., 2020). 

To do so, first author David Gate and colleagues examined substantia nigra tissue, cerebrospinal fluid, and blood samples from participants in the Alzheimer’s Disease Research Centers at Stanford University and the University of California, San Diego. They immunostained substantia nigra tissue from five Parkinson’s disease dementia (PDD) and two DLB cases, plus five controls. They looked for T cells, α-synuclein, and dopaminergic neurons. LBD tissue had more T cells than did controls, as determined by expression of the pan-T cell marker CD3. These lay next to α-synuclein aggregates and dopaminergic neurons (see image below). Gate has since started his own lab at Northwestern University, Chicago.

Cozying Up. In PDD postmortem substantia nigra tissue, a Lewy body neurite (pink) seen adjacent to a CD3 (red)-coated T cell (purple), which contacts an α-synuclein aggregate (green). [Courtesy of Gate et al., Science, 2021.]

To determine which type of T cell might have infiltrated the brains of people with LBDs, the researchers analyzed cerebrospinal fluid (CSF) from 11 healthy controls and 11 people with either PD or DLB. Single-cell RNA sequencing revealed that CD4+ T cells were most altered in LBDs, expressing large amounts of the chemokine receptor CXCR4. The data suggested that these cells are somehow being recruited into the CSF, hence the brain.

These cells also upregulated expression of a marker that goes by the mouthful “killer cell lectin-like receptor subfamily B, member 1.” CD4+ memory T cells that produce KLRB1 also make IL-17A, and indeed the researchers found IL-17A CD4+ cells in the postmortem substantia nigra. What’s more, dopaminergic neurons in the vicinity of these cells were packed with IL-17A as well (see image below).

Could α-synuclein have aroused these T cells? To test this, Gate cultured peripheral blood mononuclear cells (PBMCs)—a collection of T cells, other lymphocytes, and monocytes in the blood—taken from 53 PD cases and 32 controls. He added α-synuclein peptides to the cultures, then measured levels of IL-17A and CD69, a marker of T cell activation. Indeed, synuclein-exposed cells from PD cases, but not controls, ramped up production of both markers. “This suggests an important role for IL-17 in the brain during synucleinopathies,” David Sulzer, Columbia University, New York, wrote to Alzforum (full comment below).

Poised To Kill? In PDD substantia nigra tissue, a dopaminergic neuron (mauve) filled with IL-17A (green) lies beside a CD4 (red)-positive T cell (purple), which also contains the cytokine (inset expanded on right). [Courtesy of Gate et al., Science, 2021.]

How do the cells get into the brain in the first place? The key may lie in their upregulation of the CXCR4 chemokine receptor. In the meninges of the LBD tissue, the scientists found CXCL12, a ligand for this receptor. CXCL12 can be expressed by endothelial cells, and the researchers found it in substantia nigra blood vessels of the seven people who had had PDD or DLB (see image below). Compared to CSF from 84 controls, CSF from 79 PD cases had slightly more of this chemokine on average, and it tracked with levels of neurofilament light, indicating worse neuron damage with more of the chemokine. The authors concluded that CXCR4-CXCL12 signaling was associated with T cell brain entry.

Beckoning Blood Vessels? In PDD substantia nigra tissue, CXCL12 (red) decorates a blood vessel, while cells (green, white arrows) linger nearby. [Courtesy of Gate et al., Science, 2021.]

Jonathan Kipnis and Justin Rustenhoven, Washington University School of Medicine, St. Louis, noted that people with multiple sclerosis also have CXCR4+ T cells in their central nervous systems (Galli et al., 2019). “This speaks perhaps to a conserved receptor important for CNS homing of CD4+ T cells,” they wrote (full comment below).

Could these CXCR4+ T cells contribute to neurodegeneration? Gate thinks so because neurons do not make IL-17A, which means the cytokine flooding the DA neurons would have to come from an external source. Further, IL-17A kills cultured human neurons and neurons in mouse models of PD (Liu et al., 2017; Sommer et al., 2018). However, Iryna Prots, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany, thinks that the IL-17A-filled neurons might be trying to shield the brain. “This could represent a protective mechanism to eliminate excess IL-17A and restrict inflammation in the diseased CNS,” she wrote (full comment below).

The cytokine may have a nuanced role in brain health. Luísa Lopes, Instituto de Medicina Molecular, Lisbon, Portugal, and colleagues have reported that IL-17A from T cells in the meninges supports memory in healthy mice, whereas it impairs cognition in an amyloidosis model (Oct 2019 news; Brigas et al., 2021). “Gate and colleagues reinforce the idea that IL-17 levels are finely tuned to foster cognition in the steady state, but their pathophysiological dysregulation promotes neurodegeneration,” Lopes wrote (full comment below).

Complicating matters, Jordi Bové, Vall d’Hebron Research Institute, Barcelona, Spain, thinks that CD4+ T cells might not be the sole perpetrators because CD8+ T cells also make IL-17A. In support of this, the scientists found that after CD4+ cells, CD8+ cells in LBD CSF had the largest number of differentially expressed genes. They had previously reported that these cells cruise the CSF of people with PD (Jan 2020 news). Eliezer Masliah, National Institute on Aging, Bethesda, Maryland, also expected to see CD8+ T cells playing a more prominent role. “I was surprised that the CD4+ T cells developed this aggressive phenotype involving neuron damage,” he told Alzforum.

The identification of the CXCR4+ T cells may have clinical implications. Antagonists for this receptor have been developed to treat various types of cancer and HIV infection. Several are in clinical trials, and the FDA has approved one, plerixafor (De Clercq, 2019). While such drugs hold potential for treating LBD, Gate said they are not ready for clinical trials. “Though this study is the largest to date focusing on the immune system in LBD, there is still much to be learned. I’d love to see this work replicated and the connection between CXCL12 and neurodegeneration further explored in people who have LBD,” he said.

Schwartz noted that regulatory T cells also home to the brain using CXCR4-CXCL12 signaling. “Therapeutically targeting this pathway may be a double-edged sword, getting rid of both harmful T cells and helpful T regs,” she said. Gate plans to study CXCR4 antagonists in a mouse model of PD.—Chelsea Weidman Burke

Comments

    • User Profile Image Patrik Brundin
      Associate Director of the Van Andel Research Institute, and Director of the Center for Neurodegenerative Science
    • Posted:

    This fascinating study adds pieces to the puzzle regarding the role of the immune system in Lewy body diseases. The past decade has seen immune system changes in synucleinopathies go from typically being viewed as a response to the neurodegenerative disease to something that is potentially a driver in the disease process. 

    In particular, an important role of T cells is now becoming more evident, and the present study suggests that trafficking of Th17 cells into the brain might be a key event, with CXCR4-CXCL12 signaling regulating the process. If that turns out to be the case, then the already clinically approved CXCR4 antagonists might directly interfere with the pathogenesis of Lewy body disorders.

    One question is how early such a treatment would have to be applied to significantly slow the disease progression. One can imagine that therapies that target the immune system will be most effective if initiated in the disease prodrome, halting the immune system dysregulation before it sparks changes in the brain that cause irreversible damage.

    In addition to highlighting the possibility of new therapeutic targets, the current study also shows that we are only just beginning to understand the immune pathobiology of these neurodegenerative diseases. Because of the complexity of the immune system and brain interactions, future studies in both experimental animal and cell culture paradigms will be needed to dissect the cellular and molecular details of the pathogenic cascades. What are the roles of all the different T cell subtypes in synucleinopathies, and do they change as the disease progresses? What are the interactions of different immune cells and different α-synuclein conformers, both in the context of normal physiology and in disease?  Can T cells contribute to the clearance of aggregated α-synuclein? Finally, what are the most upstream triggers that start the disease process in synucleinopathies?

    While we do not have answers to these questions today, by now we must realize that neuroscientists and immunologists need to work together to solve these puzzles.

    View all comments by Patrik Brundin

  2. This nice study confirms specific types of T cells that appear in synucleinopathies. Along with the Sommer et al. paper the authors reference, this new work suggests an important role for IL-17 in the brain during these diseases. It also shows that there are differences between CSF and peripheral T cells: This could be related to the retention of specific T cells in the CNS in connection with these disorders, for example, peripheral T cells may acquire some characteristics around entry to the CNS.

    The study accentuates many questions in the field. Is synuclein itself the major antigen or are there additional ones? Do the T cells actually kill the neurons and, if so, what are the steps? In this context, the authors have antibody evidence that the neurons may express IL-17 themselves, and it is possible, though not shown, that they have the IL-17 receptor? So far we have only clearly seen MHC-I as a T cell receptor on genuine SN neurons, but there is much to be discovered.

    Overall in this field of investigation, we share the realization that these are very disease stage-specific phenomena. By the time a patient is diagnosed with PD or LBD, there may have already been a series of changes in T cell type, as well as in expression of relevant proteins by antigen-presenting cells—which may include neurons, but certainly include astrocytes and the CNS equivalents of professional APCs—and by the cells around the vasculature that control entry and exit of peripheral cell types. Thus, for the time being, it will be important to study cellular and animal models as well as people who may be in preclinical stages of these disorders.

    View all comments by David Sulzer

  3. This very interesting paper expands our knowledge of the mechanisms underlying T cell homing to the CNS and border tissues during Lewy body dementias, and it builds on previous works demonstrating a role for Th17 cells in neurodegeneration. Identifying the factors and sites underlying CNS T cell trafficking in human patients, and their resulting phenotypes, is critical to our understanding of their roles in diverse neurodegenerative disorders.

    The authors show that the CXCL12-CXCR4 axis is implicated in CD4 T cell CNS trafficking, adding to other bodies of work showing a T helper cell signature with CXCR4 induction in multiple sclerosis patients (Galli et al., 2019). This speaks perhaps to a conserved receptor important for CNS homing of CD4 T cells.

    We also found this axis to be critical for migration of these cells to CNS border tissues under homeostasis (Rustenhoven et al., 2021). Importantly, many other immune cells, including B cells, monocytes, and neutrophils use this chemokine-receptor pair for trafficking and retention. Manipulation of this axis could have further beneficial effects through attenuated CNS infiltration of diverse innate and adaptive populations following the CXCL12 induction occurring in Parkinson’s disease patients.

    It will be intriguing to further explore the actual site(s) for T cell trafficking in Parkinson’s disease and dementia with Lewy bodies. The findings that CXCR4+ T cells were present in the meninges, and that CSF levels of CXCL12 were elevated in Parkinson’s disease patients, suggest that aside from a blood route, infiltration via dural- or choroid plexus-resident T cells could be additional routes for CNS entry.

    Given the ability of these sites to enable presentation of CNS antigens, it would be interesting to observe whether these border sites house similar clonal expansion of CD4 T cells observed in the CSF during Lewy body dementias, whether these cells are transcriptionally more comparable to the CSF-unique cells than those in circulating blood, and whether presentation of α-synuclein peptides could be occurring in these regions to promote their IL-17a induction.

    References:

    Galli E, Hartmann FJ, Schreiner B, Ingelfinger F, Arvaniti E, Diebold M, Mrdjen D, van der Meer F, Krieg C, Nimer FA, Sanderson N, Stadelmann C, Khademi M, Piehl F, Claassen M, Derfuss T, Olsson T, Becher B. GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis. Nat Med. 2019 Aug;25(8):1290-1300. Epub 2019 Jul 22 PubMed.

    Rustenhoven J, Drieu A, Mamuladze T, de Lima KA, Dykstra T, Wall M, Papadopoulos Z, Kanamori M, Salvador AF, Baker W, Lemieux M, Da Mesquita S, Cugurra A, Fitzpatrick J, Sviben S, Kossina R, Bayguinov P, Townsend RR, Zhang Q, Erdmann-Gilmore P, Smirnov I, Lopes MB, Herz J, Kipnis J. Functional characterization of the dural sinuses as a neuroimmune interface. Cell. 2021 Jan 18; PubMed.

    View all comments by Jonathan Kipnis View all comments by Justin Rustenhoven

  4. In recent years, several paradigm-breaking studies revealed that T cells are functionally important in the maintenance of central nervous system (CNS) homeostasis, as well as in CNS disease conditions including neurodegeneration (Ellwardt et al., 2016).

    An involvement of T cells in Parkinson’s disease pathology, although supported by findings in animal models, cell culture, and human postmortem studies, received particular attention after a report of α-synuclein T cell reactivity in PD patients (Sulzer et al., 2017). These studies, focused on sporadic PD, triggered a more general interest in the role of the adaptive immune system in different neurodegenerative diseases.

    After previously showing a CD8+ T cell-specific signature in the blood and cerebrospinal fluid (CSF) in Alzheimer’s disease, in the present elegant study, Gate and colleagues, using different levels of evidence, demonstrate a particular pattern of CD4+ T cells, and a potential mechanism of T cell homing to the CNS, in a group of brain disorders characterized by deposition of α-synuclein aggregates and dementia, i.e., Lewy body dementia.

    Single-cell transcriptomic profiling identified a unique CSF CD4+ T cell population (not present in the peripheral blood), characterized by higher levels of the chemokine receptor CXCR4 and an increased activation signature, in patients with LBD. Suggesting an important role of CXCR4 in CNS T cell homing in LBD, the presence of CD3+ T cells and CXCR4+ T cells was demonstrated in LBD brain tissue, and CSF levels of the CXCR4 ligand, CXCL12, correlated with neurodegenerative biomarkers in LBD patients. Very intriguing results of this study included the demonstation of enhanced IL-17A expression in LBD T cells after stimulation with phosphorylated α-synuclein peptide, and the presence of IL-17A-positive CD4+ T cells in the LBD substantia nigra.

    Despite the undoubtedly fascinating results, questions remain to be addressed by future studies. Is α-synuclein reactivity of T cells in LBD a late phenotype of the disease or is neurodegeneration caused/driven by an auto-immune inflammation? Is T cell activation in LBD a systemic phenomenon that also takes place in the peripheral immune organs, or is it only happening in the CNS? What signals are promoting CXCR4 expression and T cell homing to the CNS in LBD?

    The intriguing finding of a higher level of IL-17A in LBD substantia nigra and an increased IL-17A production by LBD T cells in responce to α-synuclein stimulation, which was not observed in PD studies, begs the question whether an α-synuclein-driven Th17 response might be specific for CNS conditions, characterized by dementia. Another question is: Might the increased IL-17/Th17 response be responsible for an increased risk of developing neurodegenerative diseases by patients with autoimmune inflammatory conditions? The close proximity of CD3+ T cells to α-synuclein deposits and dopaminergic neurons in LBD patients‘ brain tissue, as reported in this study, points toward a direct T cell interaction with neurons, possibly involving α-synuclein. In this respect, an important unsolved question is: Does increased reactivity of LBD and PD T cells to α-synuclein peptide(s) and a specific disease-related T cell signature drive neuronal damage? If so, by which mechanism? Are the auto-reactive T cells the ones able to migrate into the CNS and interact with neural cells under diseased conditions?

    Uncovering the mechanisms and activation pattern(s) of the peripheral immune system in neurodegenerative disorders has a great translational potential, but it needs to be acompanied by investigations of functional consequences of immune cell alterations on CNS cells and their possible direct interation in order to understand a complete pathological picture of the disease.

    References:

    Ellwardt E, Walsh JT, Kipnis J, Zipp F. Understanding the Role of T Cells in CNS Homeostasis. Trends Immunol. 2016 Feb;37(2):154-165. Epub 2016 Jan 14 PubMed.

    Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A. T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature. 2017 Jun 29;546(7660):656-661. Epub 2017 Jun 21 PubMed.

    View all comments by Iryna Prots
    • User Profile Image Luisa V. Lopes
      Instituto de Medicina Molecular, Fac Medicine Lisbon
    • Posted:

    Neuroinflammation, characterized by increased proinflammatory cytokines, infiltrating immune cells, and activated glial cells, is increasingly recognized as a prominent player in neurodegeneration. However, the role of the immune system is not limited to the brain parenchyma, as it comprises complex interactions between the central nervous system (CNS) and the peripheral systems (Louveau et al., 2015). For instance, T cells, B cells, dendritic cells, innate lymphoid cells, and natural killer (NK) cells reside in the healthy meninges—a direct interface between the brain parenchyma and the peripheral organs. Importantly, immune cells and their soluble mediators, namely cytokines, play a key role in CNS function by modulating neuronal connectivity and thus impacting on sensory function, social behavior, as well as learning and memory (Ribeiro et al., 2019). 

    The present paper sheds new light on the neuroimmune link in Parkinson's and Lewy body disease by implicating Th17 cells in the degeneration of neurons in PD-LBD patients. More importantly, it revealed CD3+T cells home close to neurons that display α-synuclein deposits, not only in substantia nigra, but also in hippocampal CA2 neurons, which are related to learning and memory.

    The authors identified an antigenic α-synuclein epitope that promoted clonal expansion of T cells, resulting in elevated levels of IL-17A, a pro-inflammatory cytokine involved in autoimmune diseases. To uncover the mechanism of brain entry, the authors performed single-cell RNA sequencing of the cerebrospinal fluid (CSF) from healthy and PD-LBD patients and found that the chemokine receptor CXCR4 is upregulated in CD4+ T cells in the CSF of PD-DLB patients. Its ligand, CXCL12, was expressed in the cerebrovasculature, with higher levels correlated with severity of cognitive impairment, and CD3+ T cells resided in the perivascular space adjacent to CXCL12+ vessels.

    Dementia with Lewy bodies and Parkinson's disease-dementia, although sharing many clinical, neurochemical, and morphological features, are two entities of major neurocognitive disorder with Lewy bodies of unknown etiology. Despite considerable clinical overlap, their diagnosis is based on an arbitrary distinction between the time of onset of motor and cognitive symptoms, i.e., dementia often preceding parkinsonism in DLB versus onset of cognitive impairment after onset of motor symptoms in PDD. Both are characterized morphologically by widespread cortical and subcortical α-synuclein/Lewy body plus Aβ and tau pathologies.

    γδ T cells are a major source of interleukin-17A (IL-17) in the healthy meninges, which promotes specifically short-term memory by supporting glutamatergic synaptic plasticity of CA1 hippocampal neurons (Ribeiro et al., 2019). However, in pathology, IL-17-producing cells, mostly γδ T cells, accumulate in the CNS at the onset of cognitive deficits and persist throughout disease progression. Very recently, we have proposed that elevated levels of IL-17 at early stages of Alzheimer’s disease contribute to synaptic dysfunction and short-term memory deficits (Brigas et al., 2021; Da Mesquita, 2018). Altogether, these findings suggested that IL-17 may be instrumentally involved in various neurodegenerative diseases.

    Indeed, in a rodent model of Parkinson’s disease (PD), Th17 cells were described to exacerbate neuroinflammation and neurodegeneration (Liu et al., 2017), which may derive from the elevated production of IL-17 by CD4+ T cells in patients with PD (Sommer et al., 2018). Moreover, recent studies have found that a defined set of peptides derived from α-synuclein act as antigenic epitopes and promote T cell responses in non-demented PD patients ex vivo (Lindestam Arleham, 2020). 

    Studies like the one now published in Science are of crucial importance to understand the impact of IL-17 on brain function at the onset and during the course of cognitive impairment. Given the pro-cognitive role of IL-17 in healthy meninges, this paper reinforces the idea that IL-17 levels are finely tuned to foster cognition in the steady state, but their pathophysiological dysregulation promotes neurodegeneration.

    Moreover, the identification of the CXCR4- CXCL12 signaling axis as a potential therapeutic target for LBD is very promising, since several CXCR4 antagonists are currently approved for clinical use to treat a wide variety of diseases. This study highlights the potential of repurposing such drugs to inhibit trafficking of pathological Th17 cells into the PD-LBD brain.

    References:

    Lindestam Arlehamn CS, Dhanwani R, Pham J, Kuan R, Frazier A, Rezende Dutra J, Phillips E, Mallal S, Roederer M, Marder KS, Amara AW, Standaert DG, Goldman JG, Litvan I, Peters B, Sulzer D, Sette A. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson's disease. Nat Commun. 2020 Apr 20;11(1):1875. PubMed.

    Brigas HC, Ribeiro M, Coelho JE, Gomes R, Gomez-Murcia V, Carvalho K, Faivre E, Costa-Pereira S, Darrigues J, de Almeida AA, Buée L, Dunot J, Marie H, Pousinha PA, Blum D, Silva-Santos B, Lopes LV, Ribot JC. IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer's disease. Cell Rep. 2021 Aug 31;36(9):109574. PubMed.

    Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. 2018 Aug;560(7717):185-191. Epub 2018 Jul 25 PubMed.

    Liu Z, Huang Y, Cao BB, Qiu YH, Peng YP. Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease. Mol Neurobiol. 2017 Dec;54(10):7762-7776. Epub 2016 Nov 14 PubMed.

    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337-41. Epub 2015 Jun 1 PubMed.

    Ribeiro M, Brigas HC, Temido-Ferreira M, Pousinha PA, Regen T, Santa C, Coelho JE, Marques-Morgado I, Valente CA, Omenetti S, Stockinger B, Waisman A, Manadas B, Lopes LV, Silva-Santos B, Ribot JC. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019 Oct 11;4(40) PubMed.

    Sommer A, Maxreiter F, Krach F, Fadler T, Grosch J, Maroni M, Graef D, Eberhardt E, Riemenschneider MJ, Yeo GW, Kohl Z, Xiang W, Gage FH, Winkler J, Prots I, Winner B. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease. Cell Stem Cell. 2018 Jul 5;23(1):123-131.e6. PubMed.

    View all comments by Luisa V. Lopes

  6. To date, postmortem brain studies examining the role of the immune system in Lewy body dementia (LBD) have focused on the innate immune system, particularly on the role of microglial cells in this disease. These studies have generally found little evidence of activation of these cells in DLB. Does this mean that the innate immune system has little role to play in LBD? The answer is given in this intriguing paper.

    We (Amin et al., 2020) and others (Castellani et al., 2011) have shown evidence of increased T cell recruitment into the postmortem brains of individuals of LBD compared with control subjects, but this paper goes much further. In a study that examined the brains of healthy aged controls, Parkinson's disease, and a mixed group of LBD and PDD, the authors confirmed evidence of increased T cell infiltration into LBD brains that showed a remarkably close proximity to the key neuropathological features of the disease, i.e., dopaminergic neurons, α-synuclein deposits, and Lewy neurites in the substantia nigra.

    Examination of CD4+ T cells in the CSF of LBD subjects showed an upregulation of a number of genes associated with cytokine production (notably IL-17; a marker of a subset of CD4+ cells known as Th17 cells) and a CSF unique signature that included the chemokine CXCR4. Brain immunohistochemistry further showed that CXCR4 and its ligand CXCL12 were expressed in the meninges and the cerebrovasculature of PPD brains and that CXCL12 in the CSF was positively correlated with a number of CSF neurodegenerative markers including neurofilament light. These results implicate that the CXCR4-CXCL12 signalling pathway is acting to recruit Th17 cells into the brain, which have subsequent involvement in the degeneration of neurons.

    The study does make the assumption that the pathogeneses for DLB and PDD are the same, which may not be the case. More importantly, it points the way to new therapeutic options, including CXCR4 antagonists. Moreover, it highlights the importance of the innate immune system in the development of these diseases.

    References:

    Amin J, Holmes C, Dorey RB, Tommasino E, Casal YR, Williams DM, Dupuy C, Nicoll JA, Boche D. Neuroinflammation in dementia with Lewy bodies: a human post-mortem study. Transl Psychiatry. 2020 Aug 3;10(1):267. PubMed.

    Castellani RJ, Nugent SL, Morrison AL, Zhu X, Lee HG, Harris PL, Bajić V, Sharma HS, Chen SG, Oettgen P, Perry G, Smith MA. CD3 in Lewy pathology: does the abnormal recall of neurodevelopmental processes underlie Parkinson's disease. J Neural Transm. 2011 Jan;118(1):23-6. PubMed.

    View all comments by Clive Holmes View all comments by Jay Amin
    • User Profile Image Jordi Bové
      Vall d'Hebron Research Institute
    • Posted:

    Using human CSF cells and postmortem human tissue, as Gate and collaborators have done here, is the best way to approach the question of how the adaptive immune system is involved in Parkinson's disease and dementia with Lewy bodies.

    As we and others have shown, human brain contains tissue-resident memory T cells. If we assume that brain parenchyma, perivascular spaces, and the spinal canal are communicating vessels, and that T cells freely circulate through these compartments as a single tissue of residence, then CSF cells obtained from a lumbar puncture are mirroring what is going on the brain parenchyma. A strong point of this work is the single-cell RNA-Seq analysis that is giving us phenotypic and functional information at the same time.

    Surprisingly, this study neglected CD8 T cells. We recently showed that CD8, but not CD4, T cells infiltrate the substantia nigra not only in diagnosed PD cases but also at an early premotor stage. We showed that nigral CD8 T cell infiltration precedes neuronal loss and α-synuclein aggregation, suggesting that α-synuclein-derived antigens are not involved, at least in the initial immune response (Galiano-Landeira et al., 2020).

    Gate and collaborators did not immunostain human postmortem tissue sections for CD4 T and CD8 T cells, and they just determine the densities of CD3-positive cells. Thus, they cannot conclude that CD4 T cell parenchymal densities are increased in LBD, or that CD4 T cells are in contact or close to α-synuclein aggregates or dopaminergic neurons.

    In addition, in my view the postmortem tissue results do not suggest that increased interleukin-17 CD4 T cells contribute to neurodegeneration in Lewy body dementia, because IL-17 can also be produced by some CD8 T cells called Tc17 and γδ T cells, among others. However, the increase of intraneuronal IL-17 immunoreactivity that the authors found is striking and intriguing.

    In the single-cell RNA-Seq analysis, the authors found that CD4 T cells from CSF were the cell type with highest number of differentially expressed genes (DEGs). CD8 T cells were the second cellular type with more DEGs, around 250. They showed higher levels of clonality compared to CD4 T cells. This result also points at the relevance of CD8 T cells. Remarkably, CXCR4 CD4 T cells from CSF had a different signature from the CD4 T cells obtained from blood. This unique phenotype should make us question if PBMC are the best source of T cells to elucidate the antigen involved in the immune attack.

    Elucidating the antigen, or antigens, that trigger deleterious and protective immune responses in those synucleinopathies is crucial to understanding their etiopathogenesis and developing preventive and therapeutic strategies. Although α-synuclein-derived antigens have long been suggested as candidates, mounting evidence suggests that T cells from control subjects also are activated in front of distinct α-synuclein epitopes.

    Sulzer and collaborators showed several years ago that those epitopes elicited mainly a Th2 response (Sulzer et al., 2017; Erratum: Sulzer et al., 2017). It is surprising that the same phosphorylated antigen that Gate and collaborators showed to elicit a Th17 response in two Lewy body dementia patients, Sulzer and collaborators found was mainly triggering IL-5 secretion (or, less frequently, IFN-γ) in PD patients. In a more recent publication, α-synuclein epitopes failed to elicit any response in a relevant percentage of PD patients included in the study, which also showed both control and PD patients to elicit a stronger response to tau than α-synuclein epitopes (Lindestam Arlehamn et al., 2019). Therefore, it seems that bearing autoreactive T cells is not necessarily pathogenic.

    As mentioned above, our recently published postmortem study suggests that CD8 T cells initiate and propagate neuronal loss in PD, and that α-synuclein-derived antigens are not what recruits them at the onset of the diseases. We cannot rule out that at some point, α-synuclein triggers distinct cellular and humoral immune responses. In fact, we found in some PD cases an increase of CD4 T cells density in the perivascular space. Those T cells are probably modulating the immune response.

    References:

    Galiano-Landeira J, Torra A, Vila M, Bové J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease. Brain. 2020 Dec 1;143(12):3717-3733. PubMed.

    Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A. T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature. 2017 Jun 29;546(7660):656-661. Epub 2017 Jun 21 PubMed.

    Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Arlehamn CS, Sette A. Erratum: T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature. 2017 Sep 13;549(7671):292. PubMed.

    Lindestam Arlehamn CS, Pham J, Alcalay RN, Frazier A, Shorr E, Carpenter C, Sidney J, Dhanwani R, Agin-Liebes J, Garretti F, Amara AW, Standaert DG, Phillips EJ, Mallal SA, Peters B, Sulzer D, Sette A. Widespread Tau-Specific CD4 T Cell Reactivity in the General Population. J Immunol. 2019 Jul 1;203(1):84-92. Epub 2019 May 13 PubMed.

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References

News Citations

  1. Trigger Warning: α-Synuclein Sets Off T Cells in Parkinson’s
  2. Do Immune Cells in the Meninges Help with … Memory?
  3. Attack of the Clones? Memory CD8+ T Cells Stalk the AD, PD Brain

Paper Citations

  1. Amin J, Holmes C, Dorey RB, Tommasino E, Casal YR, Williams DM, Dupuy C, Nicoll JA, Boche D. Neuroinflammation in dementia with Lewy bodies: a human post-mortem study. Transl Psychiatry. 2020 Aug 3;10(1):267. PubMed.
  2. Galiano-Landeira J, Torra A, Vila M, Bové J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease. Brain. 2020 Dec 1;143(12):3717-3733. PubMed.
  3. Lindestam Arlehamn CS, Dhanwani R, Pham J, Kuan R, Frazier A, Rezende Dutra J, Phillips E, Mallal S, Roederer M, Marder KS, Amara AW, Standaert DG, Goldman JG, Litvan I, Peters B, Sulzer D, Sette A. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson's disease. Nat Commun. 2020 Apr 20;11(1):1875. PubMed.
  4. Galli E, Hartmann FJ, Schreiner B, Ingelfinger F, Arvaniti E, Diebold M, Mrdjen D, van der Meer F, Krieg C, Nimer FA, Sanderson N, Stadelmann C, Khademi M, Piehl F, Claassen M, Derfuss T, Olsson T, Becher B. GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis. Nat Med. 2019 Aug;25(8):1290-1300. Epub 2019 Jul 22 PubMed.
  5. Liu Z, Huang Y, Cao BB, Qiu YH, Peng YP. Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease. Mol Neurobiol. 2017 Dec;54(10):7762-7776. Epub 2016 Nov 14 PubMed.
  6. Sommer A, Maxreiter F, Krach F, Fadler T, Grosch J, Maroni M, Graef D, Eberhardt E, Riemenschneider MJ, Yeo GW, Kohl Z, Xiang W, Gage FH, Winkler J, Prots I, Winner B. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease. Cell Stem Cell. 2018 Jul 5;23(1):123-131.e6. PubMed.
  7. Brigas HC, Ribeiro M, Coelho JE, Gomes R, Gomez-Murcia V, Carvalho K, Faivre E, Costa-Pereira S, Darrigues J, de Almeida AA, Buée L, Dunot J, Marie H, Pousinha PA, Blum D, Silva-Santos B, Lopes LV, Ribot JC. IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer's disease. Cell Rep. 2021 Aug 31;36(9):109574. PubMed.
  8. De Clercq E. Mozobil® (Plerixafor, AMD3100), 10 years after its approval by the US Food and Drug Administration. Antivir Chem Chemother. 2019 Jan-Dec;27:2040206619829382. PubMed.

Further Reading

Papers

  1. Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 2009 Jan;119(1):182-92. PubMed.
  2. Singhania A, Pham J, Dhanwani R, Frazier A, Rezende Dutra J, Marder KS, Phillips E, Mallal S, Amara AW, Standaert DG, Sulzer D, Peters B, Sette A, Lindestam Arlehamn CS. The TCR repertoire of α-synuclein-specific T cells in Parkinson's disease is surprisingly diverse. Sci Rep. 2021 Jan 11;11(1):302. PubMed.
  3. Surendranathan A, Su L, Mak E, Passamonti L, Hong YT, Arnold R, Vázquez Rodríguez P, Bevan-Jones WR, Brain SA, Fryer TD, Aigbirhio FI, Rowe JB, O'Brien JT. Early microglial activation and peripheral inflammation in dementia with Lewy bodies. Brain. 2018 Dec 1;141(12):3415-3427. PubMed.
  4. Storelli E, Cassina N, Rasini E, Marino F, Cosentino M. Do Th17 Lymphocytes and IL-17 Contribute to Parkinson's Disease? A Systematic Review of Available Evidence. Front Neurol. 2019;10:13. Epub 2019 Jan 24 PubMed.
  5. Chu T, Shields LB, Zhang YP, Feng SQ, Shields CB, Cai J. CXCL12/CXCR4/CXCR7 Chemokine Axis in the Central Nervous System: Therapeutic Targets for Remyelination in Demyelinating Diseases. Neuroscientist. 2017 Dec;23(6):627-648. Epub 2017 Jan 10 PubMed.
  6. Lindestam Arlehamn CS, Dhanwani R, Pham J, Kuan R, Frazier A, Rezende Dutra J, Phillips E, Mallal S, Roederer M, Marder KS, Amara AW, Standaert DG, Goldman JG, Litvan I, Peters B, Sulzer D, Sette A. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson's disease. Nat Commun. 2020 Apr 20;11(1):1875. PubMed.

Primary Papers

  1. 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.

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