After activation, CD4+ helper T (TH) cells differentiate into distinct effector lineages. Although CXCR5+ follicular TH (TFH) cells are important in humoral immunity, their developmental regulation is unclear. Here we show that TFH cells have a distinct gene expression profile from other effector T cells and develop in vivo independent of the TH1 or TH2 lineages. TFH cell generation is regulated by B7h expressed on B cells and, similar to TH17 cell development, is dependent on IL-21, IL-6 and STAT3. However, differentiation of TFH cells, unlike TH17 cells, does not require TGFβ signaling or TH17-specific orphan nuclear receptors RORα and RORγ in vivo. Finally, naïve T cells activated in vitro in the presence of IL-21 but not TGFβ signaling preferentially acquire TFH gene expression and function to promote germinal center reactions in vivo. This study thus demonstrates TFH as a distinct lineage of effector TH differentiation.

Abnormal neuronal aggregation of ␣-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive ␣-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial ␣-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that ␣-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of ␣-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human ␣-synuclein. Furthermore, astrocytes that were exposed to neuronal ␣-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of ␣-synuclein. Together, these results suggest that astroglial ␣-synuclein pathology is produced by direct transmission of neuronal ␣-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.

Abnormal aggregation of α-synuclein and sustained microglial activation are important contributors to the pathogenic processes in Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro, and in vivo approaches, we show that extracellular α-synuclein released from neuronal cells is an endogenous agonist for toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. TLR2 ligand activity of α-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric α-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.

Aging induces gradual yet massive cell death in higher organisms, including annual plants. Even so, the underlying regulatory mechanisms are barely known, despite the long-standing interest in this topic. Here, we demonstrate that ORE1, which is a NAC (NAM, ATAF, and CUC) transcription factor, positively regulates aging-induced cell death in Arabidopsis leaves. ORE1 expression is up-regulated concurrently with leaf aging by EIN2 but is negatively regulated by miR164. miR164 expression gradually decreases with aging through negative regulation by EIN2, which leads to the elaborate up-regulation of ORE1 expression. However, EIN2 still contributes to aging-induced cell death in the absence of ORE1. The trifurcate feed-forward pathway involving ORE1, miR164, and EIN2 provides a highly robust regulation to ensure that aging induces cell death in Arabidopsis leaves.

No abstract