Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells.

Multiple sclerosis (MS) is an inflammatory disease of the CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons, and axons. Historically, MS has been thought to be a CD4 T cell-mediated autoimmune disease of CNS white matter. However, recent studies identified CD8 T cell infiltrates and gray matter lesions in MS patients. These findings suggest that CD8 T cells and CNS Ags other than myelin proteins may be involved during the MS disease process. In this article, we show that CD8 T cells reactive to glial fibrillary acidic protein (GFAP), a protein expressed in astrocytes, can avoid tolerance mechanisms and, depending upon the T cell-triggering event, drive unique aspects of inflammatory CNS autoimmunity. In GFAP-specific CD8 TCR-transgenic (BG1) mice, tissue resident memory-like CD8 T cells spontaneously infiltrate the gray matter and white matter of the CNS, resulting in a relapsing-remitting CNS autoimmunity. The frequency, severity, and remissions from spontaneous disease are controlled by the presence of polyclonal B cells. In contrast, a viral trigger induces GFAP-specific CD8 T effector cells to exclusively target the meninges and vascular/perivascular space of the gray and white matter of the brain, causing a rapid, acute CNS disease. These findings demonstrate that the type of CD8 T cell-triggering event can determine the presentation of distinct CNS autoimmune disease pathologies.

Recent progress in polymorphism-based population genetic inference.

The recent availability of whole-genome sequencing data affords tremendous power for statistical inference. With this, there has been great interest in the development of polymorphism-based approaches for the estimation of population genetic parameters. These approaches seek to estimate, for example, recently fixed or sweeping beneficial mutations, the rate of recurrent positive selection, the distribution of selection coefficients, and the demographic history of the population. Yet despite estimating similar parameters using similar data sets, results between methodologies are far from consistent. We here summarize the current state of the field, compare existing approaches, and attempt to reconcile emerging discrepancies. We also discuss the biases in selection estimators introduced by ignoring the demographic history of the population, discuss the biases in demographic estimators introduced by assuming neutrality, and highlight the important challenge to the field of achieving a true joint estimation procedure to circumvent these confounding effects.

ChlR1 is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance.

Autonomously replicating DNA viruses must evade mitotic checkpoints and actively partition their genomes to maintain persistent infection. The E2 protein serves these functions by tethering papillomavirus episomes to mitotic chromosomes; however, the mechanism remains unresolved. We show that E2 binds ChlR1, a DNA helicase that plays a role in sister chromatid cohesion. The E2 mutation W130R fails to bind ChlR1 and correspondingly does not associate with mitotic chromosomes. Viral genomes encoding this E2 mutation are not episomally maintained in cell culture. Notably, E2 W130R binds Brd4, which reportedly acts as a mitotic tether, indicating this interaction is insufficient for E2 association with mitotic chromosomes. RNAi-induced depletion of ChlR1 significantly reduced E2 localization to mitotic chromosomes. These studies provide compelling evidence that ChlR1 association is required for loading the papillomavirus E2 protein onto mitotic chromosomes and represents a kinetochore-independent mechanism for viral genome maintenance and segregation.