Cytotoxic CD8+ T Cells as Early Drivers of Dopaminergic Neuronal Death in Parkinson’s Disease VHIR is seeking an outstanding and highly motivated postdoctoral researcher to apply for a Marie Sklodowska-Curie Postdoctoral Fellowship and join the Neurodegenerative Disorders Research Group.

Marie Skłodowska-Curie Actions – Postdoctoral Fellowships (MSCA-PF) The Marie Skłodowska-Curie Postdoctoral Fellowships (MSCA-PF) are part of the Horizon Europe programme and support postdoctoral researchers in developing an original research and innovation project through international mobility. The programme aims to strengthen researchers’ careers through excellent science, international collaboration and interdisciplinary experience, while fostering integration in both academic and non-academic environments.

The MSCA-PF call is highly competitive and represents an excellent opportunity to attract international talent and support researchers in consolidating their scientific careers through an ambitious mobility-based fellowship. The 2026 call closes on 09/09/2026 (17:00 Brussels time). For candidates applying to a European Postdoctoral Fellowship, the fellowship duration is from 12 to 24 months .

Full eligibility details: MSCA Postdoctoral Fellowships 2026 Background Parkinson’s disease (PD) is characterised by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the events that initiate their death remain unresolved. The host laboratory has generated post-mortem human evidence that places cytotoxic CD8+ T cells at the very beginning of this process.

In a systematic analysis of SNpc tissue spanning the full neuropathological spectrum of PD, CD8+ T cells were found to infiltrate the substantia nigra before α-synuclein aggregation or neuronal loss is detectable.

At the earliest presymptomatic Braak stages, when α-synuclein pathology is still confined to the olfactory bulb and brainstem, the SNpc already shows robust infiltration of CD8+ T cells—including granzyme B-expressing tissue-resident memory subsets—many of which make direct physical contacts with tyrosine hydroxylase-positive dopaminergic neurons. CD4+ T cells do not show a comparable pattern of nigral infiltration or neuronal contact. These findings, published in Brain (Galiano-Landeira et al.

, 2020), establish that a cytotoxic T cell response against dopaminergic neurons is one of the earliest detectable events in PD, raising the hypothesis that it may trigger, rather than merely accompany, the subsequent cascade of protein aggregation and neuronal death. What renders SNpc dopaminergic neurons specifically vulnerable to this CD8+ attack remains an open and fundamental question.

These neurons operate under conditions of chronic and exceptionally high oxidative stress, arising from dopamine metabolism, mitochondrial complex I insufficiency, and sustained catecholamine auto-oxidation. This intrinsic oxidative burden generates modified intracellular proteins and potential neo-antigens that may be processed and presented via MHC class I, making stressed dopaminergic neurons immunologically visible to antigen-specific CD8+ T cells.

Neuromelanin—the dark intraneuronal pigment that accumulates progressively with age as a by-product of catecholamine oxidation, uniquely abundant in human SNpc neurons—is a histological indicator of this sustained oxidative state.

The neurons that accumulate the most neuromelanin are precisely those that degenerate earliest and most severely in PD, and post-mortem data from the host laboratory show that CD8+ T cells preferentially contact neuromelanin-laden neurons, pointing to oxidative stress-associated antigenicity as a potential determinant of selective vulnerability.

To interrogate this hypothesis in a tractable experimental system, the host laboratory has developed unique rodent models in which dopaminergic neurons accumulate intraneuronal neuromelanin and replicate the oxidative microenvironment of human SNpc neurons.

Preliminary data in these animals show that CD8+ T cells infiltrate the SNpc and establish contacts with neuromelanin-accumulating neurons, closely mirroring the human post mortem findings, and providing the first experimentally tractable platform to dissect the causal role of CD8+ T cells in dopaminergic neurodegeneration in vivo. Objective The overarching goal of this project is to establish whether cytotoxic CD8+ T cells initiate, amplify, or are required effectors of dopaminergic neuronal dysfunction and death in PD.

The project builds directly on the host laboratory’s post-mortem human findings and uses unique rodent models that replicate the oxidative microenvironment of human SNpc neurons to interrogate CD8+ T cell-mediated pathology in vivo. Objective 1: Establish the causal and temporal relationship between CD8+ T cell infiltration and the earliest events of dopaminergic neuronal stress.

High-resolution immunofluorescence will quantify markers of neuronal stress (tyrosine hydroxylase downregulation, mitochondrial and lysosomal dysfunction, protein aggregation), microglial activation (Iba1, CD68), and the extent, activation state, and spatial distribution of infiltrating CD8+ T cells. Spatial transcriptomics will be applied at the earliest time point at which CD8+ infiltration is detectable, enabling in situ reconstruction of the neuron–immune transcriptional interactome at the onset of the cytotoxic response.

Objective 2: Determine whether CD8+ T cells are necessary effectors of dopaminergic neurodegeneration through antibody-mediated depletion at two critical stages: (a) the earliest time point showing tyrosine hydroxylase downregulation without overt neuronal loss, to test whether CD8+ T cells drive the transition from dysfunction to death; and (b) at the stage of maximal infiltration and neurodegeneration, to assess whether their removal can halt ongoing injury.

Outcomes will include dopaminergic neuron counts, neuronal stress markers, and microglial activation state. Objective 3: Characterise the phenotype, clonal architecture, and antigen specificity of SNpc-infiltrating and CSF-derived CD8+ T cells. Full-length single-cell immunogenomics (scRNA-seq + scTCR-seq) will be performed on CD8+ T cells isolated from the SNpc and CSF at the most informative time points.

This will define cytotoxic, exhausted, and tissue-resident memory states; reveal clonally expanded TCR repertoires indicative of antigen-driven selection; and generate convergent CDR3 motifs as candidates for computational antigen prediction. Findings will be interpreted in light of the human post-mortem TCR data generated in parallel by the host laboratory. Our Group The Neurodegenerative Diseases Research Group at VHIR is led by Dr.

Miquel Vila (ICREA Professor) and is part of CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas) and the Aligning Science Across Parkinson's Collaborative Research Network (ASAP-CRN), providing access to a broad national and international collaborative framework in basic and clinical PD research.

The host institution is the Vall d'Hebron Institut de Recerca (VHIR), the research arm of Vall d'Hebron University Hospital — the largest hospital of the Catalan Institute of Health and the main hospital of Barcelona — and a recognised leader in clinical and translational research at the European level, part of the Vall d'Hebron Barcelona Hospital Campus, a global-leading health park where research, clinical care, teaching, and innovation go hand in hand.

VHIR is a CERCA centre, accredited by the Instituto de Salud Carlos III (ISCIII), and affiliated to the Autonomous University of Barcelona (UAB). Core research facilities available to fellows include a High Technology Unit, Statistics and Bioinformatics Unit, Lab Animal Service, Biobank, and Clinical Research Support Unit, and VHIR is a member of EATRIS and ECRIN, providing access to pan-European research infrastructures.

The group’s methodological portfolio spans in vivo rodent neurobiology, human post-mortem and patient tissue analysis, multiplex immunofluorescence, spatial transcriptomics, bulk and single-cell RNA sequencing, single-cell TCR sequencing, and metatranscriptomics, with active international collaborations in neuropathology, neuroimmunology, and computational biology.

Main responsibilities and duties: The fellow will have work with experimental platforms, including neuromelanin-accumulating rodent models, human post-mortem SNpc tissue spanning the full neuropathological spectrum of PD, multiplex immunofluorescence, spatial transcriptomics, scRNA-seq, scTCR-seq, and metatranscriptomics. Training in experimental neuroimmunology, translational PD research, and single-cell genomics within a highly collaborative international environment.