Encephalitogenic T cells that mediate experimental autoimmune encephalomyelitis (EAE) are commonly assumed to be exclusively CD4+, but formal proof is still lacking. In this study, we report that synthetic peptides 35–55 from myelin oligodendrocyte glycoprotein (pMOG35–55) consistently activate a high proportion of CD8+ αβTCR+ T cells that are encephalitogenic in C57BL/6 (B6) mice. The encephalitogenic potential of CD8+ MOG-specific T cells was established by adoptive transfer of CD8-enriched MOG-specific T cells. These cells induced a much more severe and permanent disease than disease actively induced by immunization with pMOG35–55. CNS lesions in pMOG35–55 CD8+ T cell-induced EAE were progressive and more destructive. The CD8+ T cells were strongly pathogenic in syngeneic B6 and RAG-1−/− mice, but not in isogeneic β2-microglobulin-deficient mice. MOG-specific CD8+ T cells could be repeatedly reisolated for up to 287 days from recipient B6 or RAG-1−/− mice in which disease was induced adoptively with <1 × 106 T cells sensitized to pMOG35–55. It is postulated that MOG induces a relapsing and/or progressive pattern of EAE by eliciting a T cell response dominated by CD8+ autoreactive T cells. Such cells appear to have an enhanced tissue-damaging effect and persist in the animal for long periods.

Extrachromosomal circular DNA elements (EccDNAs) have been described in the literature for several decades, and are known for their broad existence across different species 1 , 2 . However, their biogenesis, and functions are largely unknown. By developing a new circular DNA enrichment method, here we purified, and sequenced full-length eccDNAs with Nanopore sequencing. We found that eccDNAs are mapped across the entire genome in a close to random fashion, suggesting a biogenesis mechanism of random ligation of genomic DNA fragments. Consistently, we found that apoptosis inducers can increase eccDNA generation, which is dependent on apoptotic DNA fragmentation followed by ligation by the DNA ligase 3. Importantly, we demonstrated that eccDNAs can function as potent innate immunostimulants in a sequence-independent, but circularity, and cytosolic DNA sensing Sting-dependent fashion. Collectively, our study not only revealed the origin, biogenesis, and immunostimulant function of eccDNAs, but also uncovered their sensing pathway and potential clinical implications in immune response.

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