Synucleinopathies comprise a group of neurodegenerative diseases characterized by abnormal deposition of ?-synuclein in neurons and glia. The most frequent synucleinopathy is Parkinson’s disease (PD), in which ?-synuclein pathology propagates throughout the brain as clinical symptoms progress [1]. Possible pathological mechanisms resulting in ?-synuclein aggregation and neurodegeneration in sporadic PD are environmental factors, mitochondrial dysfunction, oxidative stress, and neuroinflammation [2, 3]; however, the exact mechanism of ?-synuclein aggregation remains elusive.
Myeloid cells collectively describe cells derived from the bone marrow, including granulocytes and monocytes [4]. In the central nervous system (CNS), several myeloid populations are present including microglia and macrophages (in further termed CNS myeloid cells) [5]. Upon activation, in response to brain injuries or to immunological stimuli [6, 7], CNS myeloid cells undergo morphologic alterations from resting ramified CNS myeloid cells into activated amoeboid CNS myeloid cells. Activated CNS myeloid cells are further divided into classical activation (M1 phenotype), characterized by expression of pro-inflammatory genes (e.g., TNF-?, IL-1?, and ICAM), or alternative activation (M2 phenotype), indicating an anti-inflammatory phagocytic phenotype, expressing characteristic phagocytic and anti-inflammatory genes (e.g., Arg1, Lgals3, and CD200r), analogous to peripheral myeloid cells. The M2 phenotype is involved in debris clearance [8–11] and was shown to decrease pathology in multiple sclerosis (MS) and amyloid beta deposits in Alzheimer’s disease [12]. In PD, activated microglia and pro-inflammatory cytokine production were evident in human post mortem brains and animal models [13–16], although the modulation of myeloid cell activation in PD is not yet fully understood.
Besides activation of myeloid cells [17], there are indications that the adaptive immune response is also involved in PD-associated disease progression [18, 19]. A genome-wide association study (GWAS) linked sporadic PD with polymorphisms in the human leukocyte antigen (HLA) region, a locus of genes encoding for surface proteins, expressed by activated antigen presenting cells, including microglia in the brain, and interacting with T cell receptors [20]. Alterations in lymphocyte populations were determined in the peripheral blood of PD patients [17, 21]. Furthermore, T lymphocytes were shown to infiltrate the brain of PD patients and to mediate dopaminergic (DA) neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD [18]. The MPTP model is characterized by acute DA neuronal loss. Besides neuronal loss, continuous aggregation of ?-synuclein is the major hallmark of PD pathology, preceding neuronal loss. Therefore, transgenic animal models over-expressing ?-synuclein will specifically allow deciphering, whether and how adaptive immune cells are involved in the early pathological mechanism of disease progression in synucleinopathies.
Accordingly, we asked, what is the impact of lymphocytes in a mouse model for synucleinopathies over-expressing human wild-type ?-synuclein (WTS) under the murine Thy1 (mThy1) promoter [22]. Therefore, we crossed mThy1 WTS mice (WTS+) with mice containing a deletion of the Rag2 gene (Rag2?/?), which lack mature lymphocytes [23]. We demonstrate that infiltration of T lymphocytes into the CNS of WTS+ Rag2+/+ mice increased ?-synuclein pathology in the substantia nigra (SN) and striatum, while no B cells were found. The presence of T cells in WTS+ Rag2+/+ mice was strongly associated with increased levels of pro-inflammatory mediators and the M1 phenotype. In the absence of T cells, increased expression of M2 defining markers and higher frequencies of infiltrating macrophages (CD11b+ CD45hi) were found in the CNS, which could contribute to the decreased levels of ?-synuclein aggregates in WTS+ Rag2?/? mice due to increased phagocytic activity. Conversely, B cells did not affect phagocytosis activity of myeloid cells in vitro.
Our data indicate that T lymphocytes aggravate the aggregation of ?-synuclein through the modulation of the CNS myeloid cell activation state. This finding will increase the understanding of T cell-mediated inflammation in synucleinopathies.